NIH SYMPOSIUM ON PROGRANULIN AND THE TDP-43 PROTEINOPATHIES
February 4-5, 2008
Frontotemporal lobar degeneration (FTLD) is the second most common cause of early-onset dementia after Alzheimer disease (AD).1 The estimated prevalence is 9 to 15 per 100,000 for those 45 to 64 years of age.2, 3 Symptoms typically appear in midlife, and include changes in personality and social conduct, including inertia, loss of
volition and disinhibition. These changes are followed by more global cognitive decline and eventual dementia. In some cases,
FTLD is accompanied by signs of Parkinson disease or motor neuron disease (MND) or both. Pathologic investigations have revealed
at least three different forms of FTLD: FTLD with tau-positive inclusions (FTLD-tau), FTLD with tau-negative, ubiquitin-positive
inclusions (FTLD-U), and FTLD without inclusions.4
A positive family history is observed in up to 50% of all FTLD patients, indicating a strong genetic component to these disorders.3 The first disease-causing mutations were identified in 1998, in the microtubule-associated protein tau gene (MAPT) on chromosome 17q21.5 These mutations were associated with FTLD-tau pathology, but not FTLD-U pathology. In 2006 mutations associated with FTLD-U
were identified as a second gene on 17q21, the gene for progranulin (GRN).6, 7 At about the same time, the major protein component of the ubiquitin-positive inclusions in FTLD-U was identified as trans-active
response DNA-binding protein of 43-kDa molecular weight (TDP-43).8 More recently, a small subset of cases of FTLD-U have been reported that fail to show TDP-43 immunoreactivity, 9-11 suggesting additional heterogeneity in FTLD-U that requires further investigation. Moreover, it has been suggested that
terminology be developed to differentiate FTLD-U cases with TDP-43 immunoreactivity (e.g., FTLD-TDP) from those that are negative
Progress has occurred rapidly in the two years since these discoveries were made. In February 2008, NINDS held a workshop
to assess the current state of the field and determine future priorities for research on progranulin, TDP-43 and FTLD-U.
The results of that workshop are reported here.
Mutations in the gene for progranulin (GRN) in FTLD-U
Mutations in GRN are a significant contributor to the total burden of FTLD, accounting for at least as many as mutations in MAPT.12 Current data indicate that GRN mutations are responsible for 5-10% of all cases of FTLD, 13-25% of familial cases, and 25% of cases with the FTLD-U pathologic
At least 62 different pathogenic GRN mutations have been discovered so far worldwide. All of them create functional null alleles, causing reduced progranulin
expression and haploinsufficiency. The mutations are found scattered throughout the gene and are of various types, including
insertions, deletions and splice site mutations. Most of the mutations introduce a premature termination codon and lead to
degradation of mutant mRNA. Genotype-phenotype analyses to date have shown no correlation between the type or location of
GRN mutation and age of disease onset, clinical symptoms or neuropathology.13-15 Since age of onset and clinical presentation are highly variable, other genetic or environmental factors must interact with
GRN mutations to influence phenotype. Missense mutations have also been identified, but the significance of these mutations
is not yet clear.16, 17 A current database of mutations associated with FTD can be found at: http://www.molgen.ua.ac.be/ADMutations/default.cfm?MT=1&ML=0&Page=ADMDB
Behavioral variant of FTD (FTDbv) is the most common clinical phenotype associated with GRN mutations. In a recent genotype-phenotype study, for example, FTDbv was seen in 63% of cases at the time of inclusion in
the study.13 Language disorders are the next most common presenting phenotype, with progressive non-fluent aphasia (PNFA) being the most
prominent of these. PNFA is the primary clinical diagnosis in 9 to 36% of patients with GRN mutations. Patients may also exhibit extrapyramidal signs, including features of parkinsonism or corticobasal syndrome.
Visual hallucinations are also seen in a relatively high proportion (30%) of GRN mutation carriers, and it has been suggested that this symptom might help distinguish patients with GRN mutations from other FTD patients.18 In contrast to FTLD patients with MAPT mutations, those with GRN mutations rarely have motor neuron degeneration (MND).13 Patients with GRN mutations also differ from those with MAPT mutations in the nature of their language disorders, which includes PNFA, but not semantic dementia (SD).19 Age of disease onset is also earlier in GRN than in MAPT mutation carriers, but is still highly variable and cannot be used as a predictor of genotype.13 In some series disease duration is shorter in patients with GRN mutations, but this is not found in all series.20
Mutations in GRN produce a relatively consistent pattern of neuropathology.14, 15, 21 It is characterized by cerebral atrophy that is most severe in frontal and temporal lobes, but in some cases may also affect
parietal lobes. In many cases atrophy is also seen in the caudate nucleus, and some cases have pathologic changes in the
substantia nigra. All of the aforementioned brain regions show neuronal loss, astrocytic gliosis and microglial activation.
The hippocampus is also affected, with loss of pyramidal cells in a pattern consistent with hippocampal sclerosis.15
The neuropathological signature of FTLD-U is a characteristic pattern of inclusions that show ubiquitin and TDP-43 immunoreactivity,
in the form of neurites, neuronal cytoplasmic inclusions (NCI) and neuronal intranuclear inclusions (NII). In GRN mutation carriers, these changes are particularly severe in upper layers of the cortex and in the neostriatum. All cases
reported to date have had NII and most NII have a characteristic lentiform shape.14 NII are not specific to GRN-related FTLD-U, since they can be detected in cases with no family history of FTLD.15 and they are numerous in patients with valosin containing protein (VCP) mutations.22 There is a range of morphologies of NCI in FTLD-U using both ubiquitin and TDP-43 immunohistochemistry, including NCI with
crescent or ring-shapes, dense round shapes and those with a diffuse granular cytoplasmic immunoreactivity. NCI are common
in cortex, hippocampal dentate fascia and neostriatum.
While some cases of FTLD have neurodegeneration and neuronal loss in upper or lower motor neurons or both (FTLD-MND),23 most cases of FTLD-U associated with GRN mutations do not. Thus, FTLD-U due to GRN mutations can usually be distinguished from other forms of FTLD by the combination of (1) severe pathology in the superficial
neocortex and the striatum, (2) the presence of lentiform NII in these structures, (3) granular NCI in the hippocampus, and
(4) absence of lower motor neuron involvement. On the other hand, it should be cautioned that this pattern can also be detected
in cases with no family history of FTLD.
Progranulin distribution and function
Progranulin is a 593 amino acid, cysteine-rich protein that was originally identified as the precursor of smaller related
peptides referred to as granulins that were isolated from inflammatory exudates and later shown to be a product of activated
leukocytes.24 Progranulin contains six and one half conserved granulin-like domains, each consisting of tandem repeats of a 12-cysteinyl
motif.25 Extracellular proteases such as elastase can cleave progranulin to generate smaller peptides, called granulins or epithelins.26
In non-neural tissues
Progranulin is expressed in a variety of peripheral tissues as well as in the nervous system. It is particularly prominent
in epithelial and hematopoietic cells, and tends to be more highly expressed in tissues with high turnover rates (e.g., gastric
mucosa, lymphoid tissue, tumor cell lines).27, 28 Progranulin is mitogenic for epithelial cells and several kinds of cancer cells, and it also promotes tumor cell invasiveness.
29-34 Progranulin is upregulated during wound healing, and it stimulates neutrophil and macrophage infiltration and neovascularization
of wound tissue.26, 35
Progranulin and granulins also regulate inflammation, through opposing effects The balance of progranulin and granulin effects
is in turn regulated by elastase and other proteases, which cleave progranulin to form granulins and secretory leukocyte protease
inhibitor (SLPI).35 SLPI is a 14-kDa protein secreted by neutrophils and macrophages, which inhibits the generation of granulins by both binding
to progranulin cleavage sites and by direct inhibition of elastase. Hence, SLPI acts to suppress inflammation and normalize
wound healing, and is pro-tumorigenic.
In the nervous system
Progranulin is expressed in a number of different neuronal populations in the adult central nervous system, including cortical
and hippocampal pyramidal cells.36 Its distribution does not coincide with the pathology of FTLD-U, and it is not associated with NCI or neurites. It is expressed
in the cerebellum and brainstem, neither of which shows significant pathology in FTLD-U. At the cellular level, progranulin
immunoreactivity is found in neuronal perikarya, dendrites and axons. It is expressed in a punctate, vesicular pattern similar
to that seen with mitochondrial or endosomal-lysosomal markers; however, the precise subcellular localization of progranulin
in neurons is still under investigation.
Many non-neuronal cell types also express progranulin. It is especially prominent in microglia and macrophages,6 but is also present in endothelial and smooth muscle cells and in the choroid plexus and ependyma. There is little or no
progranulin immunoreactivity in oligodendrocytes or astrocytes under normal conditions, but it is expressed in reactive astrocytes,
which are thought to be the major cell type that expresses SLPI in the brain.
The function of progranulin in the normal nervous system is just starting to be explored. The one study to date characterizing
GRN knockout mice focused on behavioral phenotypes in males and reported increased levels of aggression and anxiety.37 Effects of deficiency of progranulin in aging mice have not yet been reported. In vitro studies indicate that progranulin may have neurotrophic effects. It enhances cortical and motor neuron survival, and enhances
neurite length.38 This effect is blocked by SLPI, suggesting it requires processing of progranulin to granulin. Consistent with a role in
neurodevelopment, progranulin is expressed in the neuroepithelium during the early proliferative phase, and continues to be
expressed at high levels in the forebrain during formation of the cortex.27 Given increasing evidence that some neurodegenerative disease processes start early in life, additional studies of the functions
of progranulin in the developing nervous system seem warranted.
Progranulin and nervous system disease
Progranulin mRNA levels are increased in a number of neurodegenerative disorders in which microglial activation occurs, including
lysosomal storage disorders, viral encephalitis, prion related disorders and amyotrophic lateral sclerosis (ALS).36 In Alzheimer disease (AD), both microglia and dystrophic neurites in senile plaques have high levels of progranulin immunoreactivity,
which is associated with autophagic structures at the ultrastructural level. Progranulin is upregulated in response to hypoxia
and acidotic stress in fibroblasts in culture.39 The responses of neural and glial progranulin levels to physiological stressors has not yet been reported; however, it has
been shown that astrocytic SLPI is upregulated in ischemic stroke, and that SLPI has neuroprotective effects in a rodent model
The pathogenic molecular events occurring downstream of GRN mutations in FTLD-U remain to be determined. The intracellular accumulation of pathological forms of TDP-43 is a consistent
feature of most FTLD-U cases with and without GRN mutations, and it may represent a common final pathway leading to neurodegeneration. Recent microarray analyses of the brains
of FTLD‑U patients attempted to identify other molecular contributors to the disease process. 41, 42 Among the altered genes were those that are altered in a number of other neurodegeneratives diseases as well (axon guidance,
focal adhesion, and regulation of actin cytoskeleton) and two categories that are so far unique to FTLD-U (TGF-beta signaling
and cell cycle). The unique gene pathways are of particular interest because they are involved in wound healing, a process
known to be regulated by progranulin in the periphery.
TDP-43 and the FTD/ALS Connection
Ubiquitin-positive NCI are a pathological hallmark of both FTLD-U and ALS. The major protein component of these inclusions
is TDP-43,8 a 414-amino acid nuclear protein encoded by the gene TAR DNA-binding protein (TARDBP) on chromosome 1p36.2.43 TDP-43 is ubiquitously expressed, and is involved in the regulation of gene expression and splicing.44, 45 Mutations of TARDBP segregating with disease have now been identified in a small number of ALS families.46, 47
In FTLD-U, TDP-43 undergoes pathological modifications, including phosphorylation, ubiquitination and cleavage to generate
C-terminal fragments, and is redistributed from the nucleus to the cytoplasm. Cell culture studies have shown that decreased
expression of progranulin with small inhibitory RNA can stimulate cleavage of TDP-43 by caspase 3, causing aberrant TDP-43
processing and distribution similar to that seen in diseased tissue.48 Mutagenesis of putative TDP-43 nuclear targeting sequences also recapitulates the pathological redistribution of the protein
to the cytoplasm, and the formation of insoluble aggregates.49
The TDP-43 inclusions in ALS have a similar biochemical profile as those in FTLD-U, suggesting common pathogenic mechanisms
of the two disorders.50 Consistent with this idea, a GRN variant has been identified in ALS patients and appears to affect disease progression. FTLD and ALS share common phenotypes
as well. Up to 50% of ALS patients have behavioral changes and disturbances of executive function,51 and a subpopulation of FTLD patients have electrodiagnostic or pathologic evidence of motor neuron disease 52 (although, again motor neuron disease is not a typical feature of FTLD-U due to GRN mutations). In some families FTD and ALS are also present and segregate with linkage on chromosome 9.53-55
Abnormal TDP-43-positive NCI and NII are characteristic of FTD associated with inclusion body myositis and Paget’s disease
of the bone (IBMPFD), a rare multi-system disorder that includes muscle weakness, bone disease, and (in many cases) early-onset
FTD.22, 56, 57 IBMPFD is caused by mutations in VCP on chromosome 9.58, 59 Thus, a key challenge for the future will be to identify common and unique pathogenic pathways in FTLD-U, ALS and IBMPFD.
PRIORITIES FOR FUTURE RESEARCH
1. Genetic basis of FTDGRN mutations
Non-GRN gene mutations
- Determine epidemiological studies of GRN frequency in different geographic and ethnic populations.
- Continue to determine the range of different types of mutations that are pathogenic.
- Determine whether GRN mutations are pathogenic for other neurodegenerative conditions beyond FTD.
- Determine whether GRN polymorphisms increase the risk of FTD or other neurodegenerative conditions.
- Determine the genetic and environmental factors that influence age of disease onset and phenotypic expression of GRN mutations.
- Identify other genes that could affect progranulin expression (i.e. SLPI).
- Identify the gene on chromosome 9 responsible for FTLD-MND.
- Identify genetic risk factors for sporadic FTLD-U.
- Identify additional genes for FTLD-U that can explain the remaining FTLD-U families.
2. Progranulin function in normal brain
- Confirm the role of progranulin as neuronal survival factor.
- Define the fate and metabolism of progranulin in neuronal systems.
- Define the secretory mechanism.
- Identify receptor(s) for progranulin.
- Determine normal intracellular localization.
- Develop animal and in vitro models for progranulin function and regulation in neurons and microglia.
- Understand why progranulin is high in neurons all the time instead of just after injury as in most other cells.
- Determine normal levels of progranulin in brain and other tissues and biological fluids and determine factors that influence
levels such as diurnal cycle, age, sex, other diseases, drugs.
- Develop a bioassay for progranulin levels in brain.
- Determine the toxicity, biological effects, and best delivery methods of exogenously administered progranulin, its derivatives,
and related molecules in animals.
3. Progranulin disease mechanisms
- Determine if the disease is caused by deficiency of progranulin in neurons or microglia.
- Assess microglial function and inflammatory responses in FTLD-U with and without GRN mutations.
- Determine if there is a decreased incidence of cancer or increased incidence of autoimmune disease in individuals with GRN mutations.
- Determine if progranulin has a role in primary CNS tumors.
- Understand anatomical selective vulnerability associated with progranulin deficiency produced by GRN mutations.
- Develop cell and animal models for progranulin.
- Develop a bioassay.
- Test compounds that influence progranulin expression.
4. Natural history of FTD
- Study preclinical familial FTD (i.e., with PGRN or VCP mutations) to determine earliest stages of disease.
5. Role of TDP-43 in neurodegeneration
- Determine normal functions of TDP-43 in neurons.
- Understand basic mechanisms of TDP-43 accumulation (loss of function or toxic gain of function mechanism?)
- Identify mutations and polymorphic variations in TARDBP that are pathogenic or affect risk of neurodegenerative disease (especially, FTLD and ALS).
- Define the biochemical signature of pathological forms of TDP-43 (size of C-terminal fragments, phosphorylation state, folding
conformation, aggregation state) and look for correlations with patterns of neuropathology and clinical phenotype.
- Develop antibodies against phosphorylated sites, C-terminal and N-terminal of TDP-43.
- Clarify role of TDP-43 in other neurodegenerative conditions (i.e. AD, DLB, tauopathies including Guam parkinsonism-dementia
- Develop animal and in vitro models to study TDP-43 function and effects of overexpression, mis-processing.
- Determine relationship between FTD gene abnormalities (GRN, VCP, chrom 9p) and TDP-43 metabolism (e.g. through use of model systems including cell culture, flies, worms, zebrafish, and
- Develop bioassay of levels of pathological TDP-43 in biological fluids (e.g., CSF).
- Develop biomarkers for TDP-43 in vivo (i.e. neuro-imaging ligands).
- Elucidate aggregation, disaggregation and elimination mechanisms of TDP-43.
6. Administrative recommendations
- Establish a mechanism for future funding to recruit and follow families with GRN, VCP and MAPT (and other relevant) mutations through a cross-institutional consortium that would unlikely to be amenable by current R01
- Current individual centers have only modest statistical power and there is considerable expense involved in such long-term
- A multi-institutional consortium with a common research protocol would facilitate studies, optimize resources and provide
a means to test new disease modifying therapies.
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Irina Alafuzoff, M.D., Ph.D., University of Kuopio, Kuopio, Finland
Andrew Bateman, Ph.D., McGill University, Montreal, Canada
Eileen Bigio, M.D., Northwestern University, Chicago, IL
Bradley Boeve, M.D., Mayo Clinic, Rochester, MN
Nigel Cairns, Ph.D., MRCPath, Washington University, St. Louis, MO
Alice Chen-Plotkin, M.D., University of Pennsylvania, Philadelphia, PA
Susan Dickinson, M.S., The Association for Frontotemporal Dementias, Philadelphia, PA
Dennis W. Dickson, M.D., Mayo Clinic, Jacksonville, FL
Diane DiEullis, Ph.D., NINDS/NIH, Bethesda, MD
Aihao Ding, Ph.D., Weill Medical College of Cornell University, New York, NY
Matthew Frosch, M.D., Ph.D., Massachusetts General Hospital, Boston, MA
Wendy Galpern, M.D., Ph.D., NINDS/NIH, Bethesda, MD
Felix Geser, M.D., Ph.D., University of Pennsylvania, Philadelphia, PA
Bernadino Ghetti, M.D>50, Indian Univeristy, Indianapolis, IN
Murray Grossman, M.D., University of Pennsylvania, Philadelphia, PA
Katrina Gwinn, M.D., NINDS/NIH, Bethesda, MD
Kimmo Hatanpaa, M.D., Ph.D. University of texas Southwestern, Dallas, TX
Lauren Herl, University of California, San Francisco, San Francisco, CA
Michael Hutton, Ph.D., Merck Research Laboratories, Boston, MA
Keith Josephs, M.S.T., M.D., Mayo Clinic, Rochester, MN
Aimee Kao, M.D., Ph.D., University of California, San Francisco, San Francisco, CA
Virginia Kimonis, M.D., University of California, Irvine, Orange, CA
Elise Kohn, M.D., Center for Cancer Research, NCI/NIH, Bethesda, MD
Walter Koroshetz, M.D., NINDS/NIH, Bethesda, MD
Linda Kwong, Ph.D., University of Pennsylvania, Philadelphia, PA
Virginia M.-Y. Lee, Ph.D., University of Pennsylvania, Philadelphia, PA
Ti Lin, Ph.D., NINDS/NIH, Bethesda, MD
Philip Lovett, The Association for Frontotemporal Dementias, Philadelphia, PA
Ian Mackenzie, M.D., FRCPC, University of British Columbia, Vancouver, Canada
Maria Martinez-Lage, M.D., University of Pennsylvania, Philadelphia, PA
Bruce Miller, M.D., University of California, San Francisco, San Francisco, CA
Lionel Muller Igaz, Ph.D., University of Pennsylvania, Philadelphia, PA
Manuela Neumann, M.D., Ludwig-Maximilians University, Munich, Germany
Kiyomitsu Oyanagi, M.D. Tokyo Metropolitan Institute for Neuroscience, Tokyo, Japan
Catherine Pace-Savitsky, M.A., The Association for Frontotemporal Dementias, Philadelphia, PA
Scott Pesiridis, Ph.D., University of Pennsylvania, Philadelphia, PA
Leonard Petrucelli, Ph.D., Mayo Clinic, Jacksonville, FL
Creighton Phelps, NIA/NIH, Bethesda, MD
Stuart Pickering-Brown, Ph.D., University of Manchester, Manchester, England
Rosa Rademakers, Ph.D., Mayo Clinic, Jacksonville, FL
Tamas Revesz, M.D., University College London, London, England
Beth-Anne Sieber, Ph.D., NINDS/NIH, Bethesda, MD
Stephen Snyder, Ph.D., NIA/NIH, Bethesda, MD
Michael Strong, M.D., University of Western Ontario, London, Canada
Margaret Sutherland, Ph.D., NINDS/NIH, Bethesda, MD
John Trojanowski, M.D., Ph.D., University of Pennsylvania, Philadelphia, PA
Kunihiro Uryu, Ph.D., University of Pennsylvania, Philadelphia, PA
Christine Van Broeckhoven, PhD., D.Sc., University of Antwerp, Antwerp, Belgium
Vivianna Van Deerlin, M.D., Ph.D., University of Pennsylvania, Philadelphia, PA
J.C. van Swieten, M.D., Ph.D., Erasmus Medical center, Rotterdam, The Netherlands
Jean Paul Vonsattel, M.D., Columbia University, New York, NY
Matthew Winton, Ph.D., University of Pennsylvania, Philadelphia, PA
Jiping Xiao, Ph.D., University of Pennsylvania, Philadelphia, PA