Elsevier

Revue Neurologique

Volume 169, Issue 10, October 2013, Pages 793-798
Revue Neurologique

International meeting of the French society of neurology 2013
Frontotemporal lobar degeneration and amyotrophic lateral sclerosis: Molecular similarities and differencesDégénérescences lobaires fronto-temporales et sclérose latérale amyotrophique : similiarités et différences moléculaires

https://doi.org/10.1016/j.neurol.2013.07.019Get rights and content

Abstract

In the last years, new disease proteins and genes have been identified in frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS), leading to a dramatic shift in our understanding of the molecular mechanisms underlying both conditions. The vast majority of FTLD and ALS are characterized by the abnormal accumulation of TDP-43, including genetic forms associated with mutations in the genes C9ORF72, GRN, TARDBP and VCP. The overlap in pathology and of genetic factors, particularly C9ORF72 as common cause of ALS and FTLD, provides molecular evidence that both conditions represent a spectrum of diseases sharing similar pathomechanisms. Accumulation of the protein FUS defines another subset of FTLD and ALS. However, here some striking differences have been identified. All members of the FET family (FUS, EWS, TAF15) are co-accumulating with their nuclear import receptor Transportin in FTLD-FUS which is usually not associated with FUS mutations, whilst ALS-FUS is almost always associated with FUS mutations and reveals only FUS aggregates. Together with recent data demonstrating differences in the arginine methylation status of FUS in FTLD-FUS and ALS-FUS, these findings strongly imply at least partially distinct underlying disease mechanisms in these molecular subtypes of ALS and FTLD.

Résumé

Ces dernières années l’identification de nouvelles anomalies protéiques et génétiques concernant à la fois les dégénérescences lobaires fronto-temporales (DLFT) et la sclérose latérale amyotrophique (SLA) a amené à un changement radical dans notre compréhension des mécanismes moléculaires sous-jacents. La grande majorité des DLFT et des SLA est caractérisée par l’accumulation anormale de TDP-43, y compris les formes génétiques associées aux mutations des gènes C9ORF72, GRN, TARDBP et VCP. Ce recouvrement à la fois neuropathologique et génétique, notamment avec les expansions C9ORF72 comme une cause commune, est une preuve moléculaire que DLFT et SLA appartiennent à un spectre de maladies partageant des mécanismes physiopathologiques similaires. L’accumulation anormale de la protéine FUS définit un autre sous-groupe de DLFT et de SLA. Toutefois, dans ce sous-groupe, des différences significatives ont été identifiées. Dans les cas de DLFT-FUS, qui ne sont habituellement pas associés à des mutations de FUS, toutes les protéines de la famille FET (FUS, EWS, TAF15) sont co-agrégées avec leur récepteur d’import nucléaire (Transportine1). En revanche, dans les cas de SLA-FUS, qui sont quasiment toujours causés par des mutations de FUS, les agrégats sont composés exclusivement de FUS. Ces données, ajoutées aux différences de statut de méthylation (arginine dépendante) de FUS entre DLFT-FUS et SLA-FUS, sont en faveur de mécanismes moléculaires en partie distinctes entre ces deux sous-types particuliers de DLFT et SLA.

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)

  • T. Bird et al.

    Epidemiology and genetics of frontotemporal dementia/Pick's disease

    Ann Neurol

    (2003)
  • J. Brelstaff et al.

    Transportin1: a marker of FTLD-FUS

    Acta Neuropathol

    (2011)
  • J.R. Burrell et al.

    Motor neuron dysfunction in frontotemporal dementia

    Brain

    (2011)
  • Y. Chen et al.

    Expression of human FUS protein in Drosophila leads to progressive neurodegeneration

    Protein Cell

    (2011)
  • A.S. Chen-Plotkin et al.

    Genetic and clinical features of progranulin-associated frontotemporal lobar degeneration

    Arch Neurol

    (2011)
  • Y.S. Davidson et al.

    Nuclear carrier and RNA binding proteins in frontotemporal lobar degeneration associated with fused in sarcoma (FUS) pathological changes

    Neuropathol Appl Neurobiol

    (2012)
  • D. Dormann et al.

    Arginine methylation next to the PY-NLS modulates transportin binding and nuclear import of FUS

    EMBO J

    (2012)
  • D. Dormann et al.

    ALS-associated fused in sarcoma (FUS) mutations disrupt transportin-mediated nuclear import

    EMBO J

    (2010)
  • F. Geser et al.

    Clinical and pathological continuum of multisystem TDP-43 proteinopathies

    Arch Neurol

    (2009)
  • E. Kabashi et al.

    TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis

    Nat Genet

    (2008)
  • A. Kerman et al.

    Amyotrophic lateral sclerosis is a non-amyloid disease in which extensive misfolding of SOD1 is unique to the familial form

    Acta Neuropathol

    (2010)
  • T.J. Kwiatkowski et al.

    Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis

    Science

    (2009)
  • E.B. Lee et al.

    Gains or losses: molecular mechanisms of TDP43-mediated neurodegeneration

    Nat Rev Neurosci

    (2012)
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