Parkinson’s Disease 2014: Advancing Research, Improving Lives” ("PD2014") conference took place on January 6-7, 2014. At this meeting, neuroscience researchers, physicians, public and private stakeholders, and members of the public discussed the significant challenges faced by the PD patient and research community, and together developed and refined a set of recommendations addressing the highest priorities for advancing basic, translational and clinical research on PD. (PDF, 288 kB)
|1||Define the features and natural history of prodromal PD including progression, events that underlie phenoconversion to clinically manifest PD, and biomarkers or other determinants of prodromal subtypes with the goal of providing sufficient rationale to initiate proof-of-concept prevention trials that initially target high-risk populations.|
|2||Develop effective treatments and companion biomarkers for dopa-resistant features of PD. These features include both motor symptoms, particularly gait and balance problems, such as freezing of gait, and non-motor symptoms, especially cognitive impairment, psychosis, and dysautonomia.|
|3||Characterize the long-term progression of PD and understand the mechanisms that underlie the heterogeneity in clinical presentation and rates of progression. Factors related to disease heterogeneity may include clusters of clinical features as well as biological factors such as genotype and biomarkers.|
|1||Develop patient stratification tools that define disease signatures of more homogeneous cohorts with emphasis on slow- vs. fast-progressing PD, prodromal PD, and non-motor symptoms.|
|2||Develop novel and specific PET imaging agents and assays to measure α-synuclein burden, validated in both animal models and human tissue.|
|3||Develop resources with greater power to predict efficacy and biomarker outcomes in clinical trials. These resources would include well-characterized replication sets of iPS cell lines from sporadic, dominant, and recessive PD cases.|
|1||Develop transmission models of pathologic α-synuclein and tau, and determine the mechanisms of propagation, release, and uptake of misfolded α-synuclein and tau including the role of "strains."|
|2||Elucidate the normal and abnormal function of α-synuclein and its relationship to other PD genes (e.g., ATP13A2, GBA, LRRK2, PINK1, and PARK2).|
|3||Understand how different cell populations change in their coding properties, firing patterns, and neural circuit dynamics over time; how these changes relate to behavior and motor control; and how therapeutic interventions may affect such changes.|
Abbreviations. GBA: glucocerebrosidase, iPS: induced pluripotent stem, LRRK: leucine-rich repeat kinase, PET: positron emission tomography, PINK: PTEN-induced putative kinase.
|4||Develop biomarkers of target engagement and proximal pharmacodynamic effects for use in early stage clinical trials.|
|5||Improve methods to assess long-term efficacy and potential for disease modification in clinical trials, including more efficient strategies for screening potential agent and trial design simulations to assess their performance for predicting long-term benefits.|
|6||Determine factors that facilitate public health interventions, including risk factor reduction and health services interventions for populations and individuals.|
|7||Use innovative outcome measures to evaluate motor and non-motor features, including patient- and clinician- reported outcomes that leverage emerging information technology (IT) opportunities, enhance sensitivity and specificity of measurement, and facilitate long-term follow-up of well-characterized cohorts.|
|8||Develop improved informatics capability to include investigation of how “big data” may contribute to a fuller understanding of PD, a central repository for PD trial data, a resource for trial design simulations.|
|9||Develop strategies to increase minority participation in research. These initiatives should include mechanisms to assess the effectiveness of these programs and could lead to the establishment of shared resources to facilitate minority recruitment in PD clinical trials.|
|10||Identify risk factors and pathogenic mechanisms of motor fluctuations and dyskinesias to identify novel targets for prevention and symptomatic therapy.|
|4||Develop an integrated PD knowledge base that includes data from genetic, biomarker, and clinical research, and from clinical trials with informatics support for integration of existing databases for PD and other chronic neurodegenerative diseases.|
|5||Establish consensus guidelines for preclinical therapeutic studies targeting α-synuclein to ensure appropriate use of existing models, improve replication of results across labs, and provide recommendations for future model development.|
|6||Develop intermediate markers of drug efficacy in early PD translational studies to support more efficient proof- of-concept studies.|
|7||Define the required attributes of targets emerging from basic science efforts that justify advancement into translational studies in PD.|
|8||Develop a thorough understanding of targets and pathways associated with pathogenesis and pathophysiologic mechanisms of PD with emphasis on those validated by human genetics and biology.|
|9||Investigate the relationship between converging pathways in PD, for example α-synuclein misfolding and mitochondrial function.|
|10||Develop tools for measuring pathway architecture and flux in PD and integrate findings across analytical platforms into a systems-level understanding of pathogenesis and a blueprint for effective therapeutic intervention.|
|4||Generate and characterize a panel of PD-specific iPS cells (sporadic and genetic, including isogenic lines) for “omic” (RNA sequence, proteomics, methylation, etc.) pathway analysis and other approaches.|
|5||Integrate comprehensive datasets and perform functional and genetic analyses across large datasets.|
|6||Develop approaches to exploit direct access to the human brain in individuals with PD during neurosurgical procedures such as DBS, for example using non-invasive high-resolution magnetic resonance imaging and positron emission tomography.|
|7||Develop a more detailed understanding of the genetic basis of PD.|
|8||Develop a more detailed understanding of the molecular determinants and mechanisms of α-synuclein and tau aggregation (oligomer and fibril formation), disaggregation and clearance.|
|9||Use a combination of sensor technologies and imaging to develop a more precise understanding of the neural circuit dynamics in PD to enable the development of next-generation therapeutic devices.|
|10||Develop more comprehensive understanding of the role of catabolic pathways in PD, including assessment of both the ubiquitin-proteasome and the autophagy-lysosomal systems.|
|11||Advance our understanding of neural circuits, circuit analysis techniques, PD animal models, and optogenetic and related imaging technologies to improve existing therapies and generate next-generation therapies for PD.|
Need: PD has a preclinical phase, and by the time neurologic symptoms emerge, pathologic changes in the brain are widespread. Earlier detection and intervention are needed in order to optimally intervene in the PD process. The nature and duration of prodromal PD is largely unknown, but its characterization is critical to understanding the natural history of PD and its variable clinical phenotypes. Further, understanding the phase of PD before neurologic symptoms emerge will provide the foundation for PD-modifying and prevention clinical trials. Identifying at-risk cohorts who volunteer to contribute to a repository of biological and clinical data will be essential to establishing appropriate screening paradigms and early treatment strategies.
Need: Non-motor symptoms and levodopa-resistant motor features collectively constitute a major area of therapeutic need in PD. Both non-motor symptoms and levodopa-resistant features, particularly postural instability, falls, and freezing of gait, are associated with significant morbidity and mortality, particularly in advanced PD. Non-motor symptoms of PD cover a broad clinical spectrum including cognitive impairment, psychosis, and autonomic failure and thus contribute to the clinical heterogeneity of the disease. The underlying pathophysiologic mechanisms and progression of both non-motor symptoms and levodopa-resistant motor symptoms are driven by non-dopaminergic mechanisms and are poorly understood.
In addition, there is currently no consensus on the range of non-motor symptoms that should be systematically documented and the instruments that should be used. In striking contrast to the prevalence and clinical impact of non-motor symptoms, very few randomized clinical trials have been conducted to specifically target non- motor symptoms. Identification of PD subgroups by risk for specific non-motor symptoms and development of novel interventions for treatment or prevention of non-motor symptoms would result in improved quality of life for a majority of patients with PD.
Similarly, substantial knowledge gaps remain in relation to levodopa-resistant motor symptoms, particularly gait and balance problems. Recent research has hypothesized that dysfunctional cholinergic neurons in the pedunculopontine nucleus may play a role, but attempts to modulate their activity through targeted DBS or drug therapies have been disappointing. There is an urgent need to better understand the underlying mechanisms and clinic-pathologic correlations for these symptoms.
Need: Despite the benefits of dopaminergic therapies, improvement of signs and symptoms is temporary in the setting of progressive disabilities such as cognitive impairment, psychosis, postural instability, failing speech/swallowing. A more detailed understanding of risk for more rapidly progressive disability would facilitate development of treatments intended to improve long-term outcomes for PD patients. Clinical features and biomarkers could be used to predict risk for faster progression and also to identify relatively homogeneous patient populations that may be more likely to respond to targeted therapies. In particular, there is a need for biomarkers of disease activity based on specific molecular targets, e.g., α-synuclein or amyloid-beta (Aβ), involved in PD pathogenesis both to predict progression and to measure response to treatment.
Need: In addition to safety and pharmacokinetics, early stage trials seek to determine if the experimental agent has engaged the intended biological target and had the appropriate pharmacological effect. Some of these markers may also be useful to enrich the study cohort to ensure that those subjects express the biological target at sufficient levels, e.g., amyloid imaging. Such information is critical for determining dose and regimen and supporting longer-term studies to test clinical efficacy. In the absence of these markers, it is not possible to know if the biological hypothesis was tested. Examples of targets in PD in brain tissue, other tissue, or fluids include but are not limited to α-synuclein, GBA, LRRK2, and parkin. Targets such as Aβ and tau may overlap with other neurodegenerative diseases.
Need: Since confirmatory trials of disease modification require long-term follow-up, efficient designs to screen potential agents are needed for PD, especially approaches that allow assessing more than one treatment or multiple dosages of the same treatment at the same time. Currently, when a treatment fails to show efficacy in a clinical trial, it is often not clear whether the failure was due solely to the treatment itself or also to some deficiency in the trial design or measurement of the disease implemented. As novel methods and approaches are developed, it will be important to examine the performance of the design in situations where the “truth” is known, i.e., an intervention is truly effective or not. Accomplishing this will require groups of clinicians and statisticians working collaboratively to develop and assess potential design strategies, independent of the implementation of any specific trial.
Need: The number of PD cases in the US will continue to increase with population aging, causing a huge social and economic burden; preventing PD is critical. PD is a complex disorder, with genetic and environmental determinants, providing an opportunity for identification of at-risk persons and population-wide risk reduction. PD has a long preclinical phase, providing a window of opportunity for disease-modifying interventions. Knowledge gaps that must be addressed include understanding risk and preventative factors, characteristics of latent and prodromal states, and determinants of disease progression. This knowledge is needed to develop interventions to prevent onset, or slow or stop progression.
Need: Outcomes measurement is a cornerstone of clinical research. Limitations in outcomes measurement serve as a “common denominator” resulting in limitations across the breadth of clinical research. Our understanding of PD has expanded to include motor and non-motor manifestations with greater insight into disability associated with individual symptoms, such as falls, fatigue, freezing, and cognitive impairment.
However, high-quality tools for assessment of these diverse symptoms have not been adequately investigated. Modern measurement principles provide new opportunities to improve the quality of applied outcome measures including improved sensitivity, specificity, and practicality with the use of emerging technologies.
Need: A more detailed understanding of the natural history of PD, both before and after diagnosis, and the characterization of PD subtypes would accelerate development of effective treatments. Making use of existing datasets is an efficient way to address these questions. Moreover, the design of clinical trials needs access to existing longitudinal data to model appropriately and simulate design operating characteristics. Although there are recommended common data elements and requirements for sharing data publically, the technical aspects of combining datasets across multiple sources require a considerable investment of time and expertise. PD trials and well-designed cohort studies provide the highest quality data and are a resource that needs to be preserved. Administrative data sources, such as electronic medical records, are a growing resource, but require planning to utilize.
Need: Members of ethnic and racial minorities have historically been underrepresented in PD research, and participation is substantially lower for PD than for other neurological disorders such as AD and stroke. To date, the specific barriers to minority research participation have not been successfully addressed. Greater minority participation would provide a basis to understand possible biological differences in the expression of PD and give confidence in the generalizability of research results to these populations.
Need: After chronic levodopa therapy in PD, patients develop a stereotyped pattern of motor dysfunction in which they cycle between an effectively medicated “on” state with good mobility, and an un-medicated, immobile state, in spite of frequent medication dosing and the use of levodopa extenders such as catechol-O- methyl transferase (COMT) inhibitors and slow release formulations. Excess involuntary movements, or dyskinesias often accompany the “on” state. Currently there are several symptomatic treatments for fluctuations and dyskinesias, including DBS and, potentially, continuous intestinal infusion of duodopa. The knowledge gaps in this area include the neural basis for fluctuations and dyskinesias, the neural basis for the efficacy of DBS, and the risk factors for development. A better understanding of these mechanisms will improve current symptomatic therapies and perhaps slow onset of fluctuations and dyskinesias in individuals identified as having highest risk.
Need: PD is a clinical diagnosis but there exists a need to supplement this clinical classification in order to improve sensitivity and specificity. This is further confounded, as most patients do not have an identifiable cause that can be attributed to their diagnosis. If PD indeed has different causes, then therapeutic strategies are needed that enable the selection of patients who are most likely to benefit from the intended therapeutic. Current clinical trials are powered to detect effects assuming the majority of enrolled patients are responsive, so if only a subset would potentially benefit from the test agent, the clinical trial will fail even if the agent is effective in a subset of patients.
Need: Definitive non-invasive confirmation of pathologic α-synuclein is critical to support the accuracy of clinical diagnosis and can be used in combination with CSF measures of α-synuclein, to track disease progression and to monitor the effect of targeted therapeutics. Improvements or changes in α-synuclein levels may result not only from therapies targeted directly at α-synuclein but also from other successful therapies.
Measurement of multiple α-synuclein species can be used as a pharmacodynamic marker.
Need: To move the PD field forward we need a better understanding of the underlying basic mechanisms of disease, translation of these mechanisms into potential therapies, and cutting-edge clinical trials. Because of the poor track record of translating results from preclinical rodent toxin models to results in humans, the relevance of mechanisms discovered with these models to PD has been questioned and the investment by industry in developing therapies for PD is less than it might be. Thus, an important goal will be to create tools and models that can be used to study PD biology in a human context and in turn yield results that provide more accurate guidance for PD therapeutic development.
Need: An enabling approach would be to develop PD signatures by collecting high-dimensional molecular data (e.g., whole genome sequencing, transcriptomics, epigenomics, metabolomics, proteomics, iPS cell phenotypic data), and apply systems approaches to determine whether signatures of PD emerge that have important predictive value for clinical features, such as onset, progression, symptom profile and/or can identify new pathways and targets implicated in the pathophysiology of the disease. It is anticipated that disease signatures developed at different times would reveal whether the abnormalities found in patients cluster into a single group or multiple groups. Samples from clinical trials in PD should also be mined using the approaches described above to determine the extent to which responses among different PD patients are homogeneous or heterogeneous.
Need: Development of a standard set of models and procedures will facilitate direct comparison of various preclinical studies within labs and across different labs and treatment options. For example, in the case of the α-synuclein based models, there is a confusing array of possible models with very different outcome measures.
Need: Current clinical trials for disease modification in PD are expensive, require long periods of study and large numbers of patients, and future investment in such trials, and indeed in PD therapeutic development, is jeopardized due to the lack of previous success, and the finite resources within the overall funding system.
Intermediate markers of drug efficacy could support shorter and more cost-effective proof-of-concept studies and ensure a continued investment in therapeutic development in PD.
Need: There are examples of failed high profile clinical studies of compounds in PD that have not been firmly grounded in a solid understanding of the mechanism of action of the compound tested as the intended therapeutic, or in some cases its molecular mechanism of action, and such compounds have advanced to clinical studies without any attempt at early translational studies such as target engagement or pharmacodynamics markers of drug action. There is a need to stop investment in such compounds in favor of those targets and compounds that are amenable to more rigorous translational approaches.
Need: There is a need to agree on the most compelling and key pathways that are emerging in PD and have a strong foundation in human genetics or human biology, and to focus rigorous efforts to determine the most promising of these for future therapeutic development. At the same time there is a need to identify new promising targets that have not yet been identified.
Need: There is strong evidence for both α-synuclein misfolding and mitochondrial dysfunction in PD. One key question for translational drug development is whether these are unrelated causes of PD or if these two processes intersect to cause neuron death. If the two pathways intersect, which is upstream? A similar convergence of pathways related to mitophagy has been observed for autosomal recessive PD.
Need: Many of the systems affected in PD and related diseases are dynamic, and involve protein and organelle trafficking. In contrast, the majority of studies do not examine the flux of molecules through these dynamic systems. Likewise, defects in (for example) mitochondrial homeostasis can also affect metabolism in different ways but how and where bottlenecks form in networks is largely unknown. One can think of PD mutations as promoting a change in state(s) of protein and metabolome networks. Moreover, protein modification states within crucial networks may also undergo a change in state. This involves both discovery- based quantification of networks and modifications in different cell states as well as targeted analysis of particular selected proteins and modifications.
Need: Emerging evidence implicates cell-to-cell transmission of misfolded proteins through templated recruitment as a common mechanism for the onset and progression of several neurodegenerative disorders including α-synuclein and tau proteins in PD, PD dementia (PDD) and dementia with LBs (DLB). The “transmission hypothesis” for non-prion neurodegenerative diseases provides a plausible and compelling potential explanation for the stereotypical spread of pathological aggregates in PD/PDD, DLB, and other neurodegenerative diseases. Specifically, for α-synuclein and tau, aggregate-containing lysates and/or synthetic fibrils assembled from recombinant proteins template or seed their soluble counterparts to form fibrils in cultured cells and/or living animals, even without overexpression of the disease protein in PD models. Other evidence implicates distinct conformers or “strains” of misfolded α-synuclein and tau as the molecular basis for remarkable disease heterogeneity and co-morbidities. For example, one α-synuclein strain preferentially recruited monomeric tau to seed formation of neurorfibrillary tangles (NFTs), the signature lesions of AD. NFTs also are common in PDD since a third of patients with PDD show concomitant AD pathologic changes in addition to abundant cortical LBs. However, our knowledge related to the concepts of transmission and strains is rudimentary. Hence, there is an urgent need to develop an in-depth understanding of these processes, as well as to elucidate the mechanism(s) of disease protein spread, in order to identify novel targets for PD therapies.
Need: The amount of wild type α-synuclein protein expressed appears to be a strong predictor of risk for PD, in both familial and sporadic forms of the disease. Although it is generally considered that the amount of protein expressed influences the risk of misfolding and the acquisition of abnormal, pathologic function, we do not know whether an increase in the normal function of α-synuclein also contributes to degeneration.
Aggregation may in fact lower the amount of soluble α-synuclein, reducing its function with pathologic consequences. It will also be important to understand the effects of reducing α-synuclein, since many current therapeutic approaches target the protein. In addition, changes in conformation associated with the normal function of α-synuclein may predispose it to misfolding or contribute directly to pathologic effects when misdirected to organelles with which α-synuclein does not normally associate, such as mitochondria and lysosomes. Neural activity may influence the behavior of α-synuclein, and conversely, α-synuclein may influence basal ganglia circuits. The apparent requirement for α-synuclein in 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP) toxicity further implicates the normal function of the protein in degeneration. For all of these reasons, it is essential to elucidate the normal function of this protein, which will be important even if many current theories about pathogenesis are either not correct or not relevant. It will be particularly important to elucidate the relationship of α-synuclein to other PD genes since many cause characteristic α-synuclein accumulations.
Need: Neuroscience is uncovering evidence for large-scale network activity dynamics and neuroplasticity in brain circuits, including those thought to be core circuits disabled in PD. This opens up the possibility of determining with precision how PD-related circuits encode information; become altered by experience; and react to loss of dopamine, changes in oscillatory patterning, and maladaptive anatomical and gene expression
changes in the parkinsonian state. We urgently need more information about these PD-related circuits, including as much information as possible about the specific cell types (neurons, glia) and molecules (neurotransmitters, neuromodulators, genes and epigenetic modifiers) involved in these pathways. There is an unprecedented opportunity, with the explosion of new methods coming into neuroscience and medicine, to fill the enormous gap between what we would need to know to design better therapeutics and what we actually know about PD-related circuits.
Need: Recent developments in the reprogramming of human somatic cells to pluripotency with defined factors have the potential to revolutionize the study of the underlying pathogenesis of a variety of human disorders. PD is the most common movement disorder that is due, in part, to the preferential loss of dopamine neurons. The relative selective degeneration of dopamine neurons makes PD a particularly attractive human neurodegenerative disease to establish patient-specific cells in culture. Successful implementation has the potential to transform the study and treatment of PD by providing new molecular insights into the pathogenesis of PD. Moreover, the potential discovery of biochemical and/or molecular markers ultimately could be used as biomarkers to monitor the progression of PD.
Need: There has recently been an explosion of information derived from large-scale experimental approaches in PD-focused research. These comprehensive analyses include, but are not limited to, genetic screens in model organisms, expression and epigenomic analyses in patient tissue and appropriate models (iPS cells, mouse and other mammalian models), GWAS, and large-scale drug screens. While all these approaches are
important individually, there now exists a critical unmet need to integrate comprehensive data sets to identify most effectively pathways and mechanisms that impact key disease phenotypes and pinpoint the most promising therapeutic targets.
Need: Although a number of animal models of PD have been developed and new models continue to advance, no model is yet able to recapitulate the spectrum of features, either symptoms or neuropathologic changes, or the time course of disease progression in humans with PD. Thus, it is critical to advance studies in human subjects, and several recent advances have made this possible. First, the rapid growth of functional neurosurgical procedures, especially DBS, provides unprecedented direct intraoperative access to the human brain. In parallel, continued development of non-invasive imaging modalities such as high-resolution MRI and PET – for example, the development of 7T MRI and high-resolution research tomography PET - provide approaches to quantify the structural and biochemical changes that occur during the onset and progression of PD. These reverse translation activities are essential parallel adjuncts to studies in animal models to understand, validate, and improve the relevance of these animal models for both basic science PD research and translational efforts.
Need: Genetic work in PD has expanded from its initial success in monogenic forms of the disease to include understanding of the genetic architecture of apparently idiopathic PD. The field has now put forth a major collaborative effort in genetics, resulting in the identification of 28 independent loci for disease risk. While this progress is beginning to shed insight into the basic etiologic processes (e.g., Rab-7L1 and LRRK2) more needs to be done. The immediate needs are threefold: 1) moving from our understanding that a locus is
associated with disease to proving which transcript is the biological effector of this association, 2) expanding our genetic dissection of risk, and 3) extending the genetic efforts beyond simple risk, to include disease- related traits such as age at onset, progression, presentation of motor and non-motor features, and response to treatment. While each of these will shed light on the basis of disease, the last point is essential to understand disease heterogeneity and for precision medicine for PD. The majority of these projects require large collaborative efforts.
Need: Several lines of evidence demonstrate that α-synuclein aggregation plays a central role in the etiology of PD (both familial and sporadic forms) and that tau aggregation contributes to other neurodegenerative disorders characterized by parkinsonism. However, very little is known about the structure and dynamic properties of different α-synuclein and tau aggregates such as oligomers, fibrils and LBs and NFTs, and the molecular determinants, cellular mechanisms, and pathways that regulate their formation, clearance, and toxicity. In addition, it remains to be determined what role sequence variants and post-translational modifications play in modulating these processes. Several factors contribute to this gap in knowledge, including the lack of model systems that accurately recapitulate α-synuclein and tau aggregation and accumulation of LBs and NFTs in the brains patients with parkinsonism, lack of experimental approaches to observe directly these processes; and difficulties in isolating intact α-synuclein in LBs and tau in NFTs from human brains. Filling this knowledge gap by delineating α-synuclein and tau aggregation, clearance, and functional pathways will facilitate development of novel therapies for neurodegenerative disorders characterized by parkinsonism.
formation, dissociation, and clearance in vitro, in cells, in animal models, and in human biological samples.
Need: Despite the established clinical efficacy, the mechanism of DBS in PD is incompletely understood. Because ablative neurosurgery for PD is similarly effective for treating PD, the stimulation-evoked silencing of pathologically hyperactive neurons was initially postulated as the primary mechanism. However, more recent studies have reported activation of output nuclei from DBS target structures such as subthalamic nuclei (STN) and globus pallidus interna (GPi). The neural network activation hypothesis has enormous implications for DBS mechanism of action. Indeed, DBS should evoke target-specific changes in neural activity in interconnected structures within the basal ganglia complex that ultimately underlie clinical benefit. Nevertheless, our understanding of these distal effects of DBS remains far from complete, in large part because of the technical difficulties in using imaging and sensor technologies for global assessment of neural activity in animal models and in human patients with an implanted device. Further refinement of our understanding of the mechanism of DBS is critical to enable the optimization of DBS for patients with PD.
Need: Substantial experimental evidence suggests that disturbances in cellular catabolic pathways are central to the pathogenesis of PD. Human genetic studies, cell biology approaches, and animal studies have implicated disturbances in either or both of the two major intracellular catabolic pathways: the ubiquitin-
proteasome system and the autophagy-lysosomal system. In some cases (e.g., GBA or ATP13A2) a global cellular disturbance in the catabolism of macromolecules is implicated. In other cases (e.g., PINK1 or PARK2) more discrete catabolic defects may be at work. Yet despite compelling evidence implicating catabolic defects in PD, substantial gaps in knowledge remain. Our knowledge of the normal role of PD-related genes in the functioning of catabolic pathways and how this functioning is impacted by disease variants is incomplete. The downstream consequences of catabolic pathway defects on cellular physiology relevant to PD remain to be fully elucidated. Finally, the pervasiveness of these putative defects in catabolic pathways among different subgroups of patients with PD is unclear. Interdisciplinary approaches that integrate human genetic studies with genetically tractable models, mammalian models, and emerging human iPS cell models are needed.
Need: Treatments that ameliorate symptoms of PD modify the dynamics of large-scale neural circuits. Yet, due to the complexity of the neural circuits that go awry in PD, and our still-limited understanding of their normal and pathophysiological states, more effective treatments would undoubtedly result from a clearer understanding of the circuitry and its dynamics. Recently, a new generation of technologies has emerged that collectively hold the potential to answer many of the outstanding questions about the neural circuits involved in PD. These exciting technologies include optogenetic means for activating and inhibiting specific cell types using light, imaging techniques for visualizing the dynamics of genetically defined cell types during animal behavior, computational methods for analysis of large-scale imaging data, methods of high-resolution circuit reconstruction, and genetically encoded fluorescent sensors that report neural Ca2+ excitation, voltage depolarization, or release of neurotransmitter or neuromodulator. Application of these approaches in animal models of PD will likely yield substantial insights into circuit structure and dynamics, as well as improved therapies based directly on these insights.
Last Modified April 15, 2014