International meeting of the French society of neurology 2013Frontotemporal lobar degeneration and amyotrophic lateral sclerosis: Molecular similarities and differencesDégénérescences lobaires fronto-temporales et sclérose latérale amyotrophique : similiarités et différences moléculaires
Introduction
Frontotemporal dementia (FTD) is the second commonest cause of dementias in the presenile age group (< 65 years) accounting for 5 to 15% of all dementias. FTD is a clinical syndrome, characterized by progressive deterioration in behavior, personality and/or language, with relative preservation of memory due to a predominant fronto-temporal lobar degeneration (FTLD). Clinical subtypes include behavioral variant of frontotemporal dementia (bvFTD), progressive non-fluent aphasia (PNFA) and semantic dementia (SD). A family history of dementia is present in 25 to 50% of cases, mainly with an autosomal dominant pattern of inheritance (Bird et al., 2003, Rademakers et al., 2012).
Amyotrophic lateral sclerosis (ALS) is the most common form of motor neuron disease in which the predominant loss of motor neurons from the brain and spinal cord leads to fatal paralysis and death, usually within 1 to 5 years. Most cases are sporadic, and ∼5% are familial (Mitchell and Borasio, 2007).
The clinical overlap between ALS and FTD is well established and increasingly recognized. Thirty to 50% of ALS patients show at least some executive function deficits, with 15% meeting the clinical criteria for FTD (Lomen-Hoerth et al., 2003, Ringholz et al., 2005); likewise, up to 15% of FTD patients present with motor neuron dysfunction (Lomen-Hoerth et al., 2002, Burrell et al., 2011). The molecular basis for this clinical overlap was provided by the recent advances in the molecular neuropathology and genetics of FTLD and ALS. Like most other neurodegenerative disorders, ALS and FTLD are neuropathologically characterized by the accumulation of ubiquitin-positive insoluble protein deposits forming distinct inclusion bodies in cells of the central nervous system. Historically, FTLD was subdivided into those with abnormal accumulation of the tau protein (FTLD-tau) and those with tau-negative inclusions (FTLD-U) with unknown protein identity (McKhann et al., 2001). Likewise, ubiquitinated inclusions were also recognized in ALS, with about 20% of familial ALS showing accumulation of SOD1 associated with SOD1 gene mutations (Rosen et al., 1993, Kerman et al., 2010), while the protein identity in the remaining ALS cases remained enigmatic. This issue was mainly resolved with the identification of the multifunctional DNA/RNA binding protein TDP-43 as accumulating proteins in the vast majority of FTLD-U and ALS cases (renamed as FTLD-TDP and ALS-TDP) (Neumann et al., 2006, Mackenzie et al., 2007), followed by the discovery of another DNA/RNA binding protein FUS as accumulating protein in remaining TDP-43-negative rare ALS and FTLD subtypes (renamed as FTLD-FUS and ALS-FUS) (Vance et al., 2009, Neumann et al., 2009a, Kwiatkowski et al., 2009). Based on these findings, almost all ALS and FTLD cases can now be classified into three major molecular subtypes, respectively, based on the accumulating protein(s) thought to be most characteristic and of pathogenetic relevance (Fig. 1) (Mackenzie et al., 2010a). Moreover, identification of new disease genes, such as C9ORF72, common in both clinical conditions, strongly supports the idea of ALS and FTLD as a spectrum, in which ALS and FTLD can be alternative or overlapping manifestations of the same pathomechanisms. However, also significant genetic and pathological differences are recognized with some gene defects and protein deposits being quite unique to either FTLD or ALS, suggesting at least partially divergent pathomechanisms. This review highlights the commonalities and differences in the molecular neuropathology and genetics of ALS and FTLD with focus on TDP-43 and FUS-proteinopathies.
Section snippets
Molecular pathology of FTLD-TDP and ALS-TDP
In 2006, the disease protein in the vast majority of FTLD-U cases and ALS was identified as DNA/RNA binding protein TDP-43, now renamed as FTLD-TDP and ALS-TDP (Neumann et al., 2006, Mackenzie et al., 2007, Mackenzie et al., 2010a). FTLD-TDP and ALS-TDP includes sporadic cases and genetic forms with mutations in the genes GRN, VCP, TARDBP and the recently recognized C9ORF72 repeat expansion (Fig. 1) (Rademakers et al., 2012, Cairns et al., 2007, Mackenzie et al., 2010b). TDP-43 pathology
Molecular neuropathology and genetics of ALS-FUS and FTLD-FUS
Mutations in FUS were found as the genetic cause in TDP-43-negative ALS cases accounting for ∼3% of ALS cases with the associated pathology being characterized as abnormal cytoplasmic accumulation of FUS predominantly in motor neurons (ALS-FUS) (Vance et al., 2009, Kwiatkowski et al., 2009). Subsequently, FUS was identified as the pathological protein in most of the remaining tau/TDP-43-negative FTLD subtypes, renamed as FTLD-FUS, including three closely related but distinct
Conclusion
The major pathological proteins accumulating in the central nervous system in FTLD and ALS and the most common FTLD and ALS-causing genes have now been discovered, demonstrating the complexity and heterogeneity underlying ALS and FTLD pathogenesis. With the identification of disease proteins and genes common in both clinical phenotypes, clear molecular evidence is provided for a pathogenetic overlap in ALS and FTLD. However, also important differences have been noted with some genes and
Disclosure of interest
The author declares that she has no conflicts of interest concerning this article.
Acknowledgements
The research work of the author is supported by the Helmholtz Association (W2/3 program for outstanding female scientists), the German Federal Ministry of Education and Research (01GI1005B), the Swiss National Science Foundation (31003A-132864; CRSII3 136222), the Hans and Ilse Breuer Foundation and the IFRAD Foundation.
References (47)
- et al.
Unconventional translation of C9ORF72 GGGGCC expansion generates insoluble polypeptides specific to c9FTD/ALS
Neuron
(2013) - et al.
TDP-43 in familial and sporadic frontotemporal lobar degeneration with ubiquitin inclusions
Am J Pathol
(2007) - et al.
Understanding the role of TDP-43 and FUS/TLS in ALS and beyond
Curr Opin Neurobiol
(2011) - et al.
Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS
Neuron
(2011) - et al.
A C9orf72 promoter repeat expansion in a Flanders-Belgian cohort with disorders of the frontotemporal lobar degeneration-amyotrophic lateral sclerosis spectrum: a gene identification study
Lancet Neurol
(2012) - et al.
Exome sequencing reveals VCP mutations as a cause of familial ALS
Neuron
(2010) - et al.
TDP-43 and FUS in amyotrophic lateral sclerosis and frontotemporal dementia
Lancet Neurol
(2010) - et al.
Amyotrophic lateral sclerosis
Lancet
(2007) - et al.
A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD
Neuron
(2011) - et al.
p62 positive, TDP-43 negative, neuronal cytoplasmic and intranuclear inclusions in the cerebellum and hippocampus define the pathology of C9orf72-linked FTLD and MND/ALS
Acta Neuropathol
(2011)
Epidemiology and genetics of frontotemporal dementia/Pick's disease
Ann Neurol
Transportin1: a marker of FTLD-FUS
Acta Neuropathol
Motor neuron dysfunction in frontotemporal dementia
Brain
Expression of human FUS protein in Drosophila leads to progressive neurodegeneration
Protein Cell
Genetic and clinical features of progranulin-associated frontotemporal lobar degeneration
Arch Neurol
Nuclear carrier and RNA binding proteins in frontotemporal lobar degeneration associated with fused in sarcoma (FUS) pathological changes
Neuropathol Appl Neurobiol
Arginine methylation next to the PY-NLS modulates transportin binding and nuclear import of FUS
EMBO J
ALS-associated fused in sarcoma (FUS) mutations disrupt transportin-mediated nuclear import
EMBO J
Clinical and pathological continuum of multisystem TDP-43 proteinopathies
Arch Neurol
TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis
Nat Genet
Amyotrophic lateral sclerosis is a non-amyloid disease in which extensive misfolding of SOD1 is unique to the familial form
Acta Neuropathol
Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis
Science
Gains or losses: molecular mechanisms of TDP43-mediated neurodegeneration
Nat Rev Neurosci
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