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Human Molecular Genetics 2006 15(Review Issue 2):R182-R187; doi:10.1093/hmg/ddl202
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Recent advances in the genetics of amyotrophic lateral sclerosis and frontotemporal dementia: common pathways in neurodegenerative disease

Kevin Talbot1,2,* and Olaf Ansorge3

1 Department of Physiology, Anatomy and Genetics , 2 Department of Clinical Neurology, University of Oxford and 3 Department of Neuropathology, University of Oxford, Henry Wellcome Building of Gene Function, South Parks Road, Oxford OX1 3QX, UK

* To whom correspondence should be addressed. Tel: +44 1865285875; Fax: +44 1865790493; Email: kevin.talbot{at}clneuro.ox.ac.uk

Received July 19, 2006; Accepted July 27, 2006


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 FRONTOTEMPORAL DEMENTIA
 GENETIC LINKAGE STUDIES IN...
 CHMP2B
 DYNACTIN
 VALSOLIN-CONTAINING PROTEIN
 PROGANULIN
 CONCLUSIONS
 REFERENCES
 
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease classically defined by the impairment of the voluntary motor system and ubiquitin-positive intraneuronal aggregates in anterior horn cells. Frontotemporal dementia (FTD) is a common form of neurodegenerative dementia and presents with personality change associated in a significant subgroup of patients with cortical ubiquitin-only neuropathology (FTD-U). Careful study of ALS as well as FTD patient cohorts suggests clinical as well as pathological overlap of ALS with FTD. The idea that this reflects a shared pathogenesis has received strong support from the identification of new genetic loci on chromosome 9p and of mutations in specific genes (CHMP2B and DCN1) in families with co-segregation of ALS and FTD. The identification of two further genetic causes of FTD-U with (rare) ALS (PGRN) or without ALS (VCP) also provides a starting point for exploring the pathways associated with ubiquitin-mediated protein mishandling in FTD-U and ALS. Pure ALS, through ALS with cognitive impairment and ALS–FTD to pure FTD-U, may represent a continuous spectrum of ubiquitin-associated neurodegenerative disease.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
FRONTOTEMPORAL DEMENTIA
 GENETIC LINKAGE STUDIES IN...
 CHMP2B
 DYNACTIN
 VALSOLIN-CONTAINING PROTEIN
 PROGANULIN
 CONCLUSIONS
 REFERENCES
 
Amyotrophic lateral sclerosis as a multisystem neurodegenerative disease
Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disease with a uniformly fatal outcome and is defined as a disorder in which there is both corticospinal (upper motor neuron) and spinal (lower motor neuron) involvement. Weakness and atrophy of muscles arise from denervation as a consequence of loss of motor neurons in the anterior horns of the spinal cord. Death occurs when respiratory muscle involvement leads to a critical reduction in ventilatory reserve. Underlying a wide variation in survival time and differences in clinical distribution is the observation that all cases of ALS have the unifying pathological hallmark of cytoplasmic intraneuronal ubiquitinated proteinaceous inclusions (1). Familial ALS (FALS) that is clinically indistinguishable from the sporadic form of disease has been associated with a number of genetic loci and mutations in specific genes, principally SOD1 (2) in ~20% of cases and recently in the gene for VAPB in a Brazilian population with a founder mutation (3). A number of other genetic causes have been identified in ‘ALS-like’ disorders, which are clinically atypical and pathologically distinct from typical ALS (4).

A paradigm shift in our thinking about the nature of ALS has occurred in the last decade and it is now considered to be a multisystem neurodegenerative disease in which voluntary motor pathways are the first but not the only CNS structures to be involved. It has long been recognized that a minority (2–3%) of ALS patients develop frank dementia. However, detailed cognitive testing has also revealed that up to 50% of unselected ALS patients have evidence of disturbances in executive functions such as planning, initiation and social interaction (5,6). This pattern of abnormalities is usually associated with changes in behaviour ranging from apathy and disengagement to aggression and disinhibition. The classification of ALS-associated cognitive impairment is still evolving and reflects uncertainties about whether this is a continuum or a number of discrete entities. Terms such as ‘ALS with cognitive impairment’ and ‘ALS–FTD’ may need to be revised in the future. In ALS patients with cognitive involvement, cytoplasmic ubiquitin-positive inclusions involve hippocampal and neocortical neurons in addition to anterior horn cells (7). Interestingly, in rare cases of sporadic ALS as well as FALS with unknown mutations, the cytoplasmic inclusions are complemented by intranuclear ubiquitinated aggregates (8). In general, typical ubiquitin inclusion pathology has been demonstrated with less frequency in FALS due to SOD1 mutations.


   FRONTOTEMPORAL DEMENTIA
TOP
 ABSTRACT
 INTRODUCTION
 FRONTOTEMPORAL DEMENTIA
GENETIC LINKAGE STUDIES IN...
 CHMP2B
 DYNACTIN
 VALSOLIN-CONTAINING PROTEIN
 PROGANULIN
 CONCLUSIONS
 REFERENCES
 
FTD is the second commonest form of pre-senile dementia after Alzheimer's disease and is characterized by the degeneration of the frontal and temporal lobes of the brain leading to severe change in personality, bizarre behaviour such as sudden change in preference for sweet food, impulsivity and loss of sexual and social boundaries (9). Memory impairment is often not a major feature in the initial phases, but language function is affected to a variable degree. Between 30–50% of FTD cases are familial. The syndrome of FTD has been associated with two types of pathological change, which in individual cases cannot be predicted on clinical grounds. Tau positive inclusions account for the majority of cases and most familial (but not sporadic) cases with tau pathology carry mutations in the microtubule-associated tau protein on chromosome 17 (10). The other main pathological finding in FTD is so-called ubiquitin-only pathology (i.e. negative for tau or alpha-synuclein), suggesting a link with ALS (Fig. 1).


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  		Figure 1. (A) Classical cytoplasmic ubiquitin-only pathology in the fascia dentata of the hippocampus in a patient who died of ALS with FTD. (B) Intranuclear ubiquitin-only inclusions in a patient with otherwise typical FTD-U pathology. The combination of cytoplasmic and nuclear ubiquitin-only pathology may point to specific genetic causes (see text) (mutation status of this patient is currently unknown).

 
Because of the presence of Parkinsonian features in some affected individuals, tau-associated familial FTD is known as FTDP-17T (11). The presence of tau pathology and an extended at-risk haplotype around the tau gene in sporadic neurodegenerative diseases such as progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) (12,13) have led to these conditions being grouped together with AD and FTDP-17T as ‘tauopathies’. Despite reports of occasional amyotrophy in patients and in the transgenic mouse model of FTDP-17T (14), there are no cases of typical ALS or ALS–FTD associated with tau mutations. For this reason, tau has not been considered a major component of the neuropathology of ALS, although this view may be changing because of the finding of coiled tau inclusions in the cortex of some patients with ALS and cognitive impairment (15). Curiously, a separate group of 17q-linked families has been identified, which do not have mutations in MAP-tau and are reported to have ubiquitin-only pathology. Genetic and pathological heterogeneity in FTD linked to 17q has now been clarified with the identification of mutations in progranulin described below.


   GENETIC LINKAGE STUDIES IN ALS-FRONTOTEMPORAL DEMENTIA
TOP
 ABSTRACT
 INTRODUCTION
 FRONTOTEMPORAL DEMENTIA
 GENETIC LINKAGE STUDIES IN...
CHMP2B
 DYNACTIN
 VALSOLIN-CONTAINING PROTEIN
 PROGANULIN
 CONCLUSIONS
 REFERENCES
 
From the earliest descriptions of ALS with dementia, it was recognized that this condition could be familial. In a study of 16 families with FALS in which SOD1 mutations had been excluded, Hosler et al. (16) identified a subset linked to chromosome 9q21–22. The maximum LOD score of approximately 8 was generated by the addition of smaller scores in several families, and given what is now known of the genetic heterogeneity and variable penetrance in ALS–FTD, it is possible that some of these families are in fact not linked to 9q. To date, no genetic mutations have been identified in this region and no further families have been published with linkage to 9q. Recently, however, three separate research groups have published linkage to chromosome 9p. In a large Dutch kindred which had initially shown provisional linkage to chromosome 16q12 with a LOD score of 1.84 (17), the development of ALS in two individuals in one generation, previously scored as unaffected, led to a revision of the linkage data and exclusion of 16q by haplotype analysis. Using an Affymetrix 10K SNP based chip–microarray system, a LOD score of 3.02 was subsequently identified in 9p13.3–21.3 (18). Four out of 13 individuals affected with ALS in this pedigree also had FTD and several patients underwent autopsy confirming ubiquitin-positive intraneuronal inclusions in a typical distribution for FTD–ALS, including in one individual with no clinical evidence of dementia. Further support for an FTD–ALS locus on 9p comes from a Scandinavian family in which five members died of ALS (with very mild or minimal cognitive impairment) and nine had FTD without motor neuron involvement (19). Despite two individuals having had an autopsy, no mention is made of whether this family demonstrates ubiquitin pathology. Finally, further families have recently been reported in the abstract form, but with a LOD score not greater than 2, providing additional but provisional support for 9p harbouring a major locus for ALS–FTD (20). Collectively, these reports suggest that there is a locus on 9p21, which causes both ALS and FTD, with at least some families having the same ubiquitin-positive neuropathology as sporadic ALS (Table 1).


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  		Table 1. Genetics and pathological correlates of ALS and FTD spectrum disorders

 

   CHMP2B
TOP
 ABSTRACT
 INTRODUCTION
 FRONTOTEMPORAL DEMENTIA
 GENETIC LINKAGE STUDIES IN...
 CHMP2B
DYNACTIN
 VALSOLIN-CONTAINING PROTEIN
 PROGANULIN
 CONCLUSIONS
 REFERENCES
 
A large family with FTD from the Jutland peninsula of Denmark was linked to chromosome 3 in as early as 1995 (21). Affected individuals typically present in the late 50's with disordered behaviour typical of FTD. Although a motor syndrome may develop late in the illness, there were no individuals reported with typical ALS (22). Pathology in this disorder is described as having no distinctive features, meaning that staining for tau and ubiquitin is negative. Recently, the gene for FTD3 was identified as charged multivesicular body protein 2B (CHMP2B) (23). Mutations in the splice acceptor site of exon 6 segregate with the affected phenotype in this family and lead to aberrant splicing which is detected in mRNA from affected brain as either intron inclusion or a small truncation arising from processing from a cryptic splice site. At the protein level, this is predicted to result in a 36-amino acid C-terminal truncation or replacement of the same region with an novel 29-amino acid sequence respectively. The authors screened 400 FTD cases (89 familial) and found one further, apparently sporadic, case with a D148Y substitution in CHMP2B. A large screen of 141 individuals with familial FTD from the US and UK also failed to reveal any mutations in CHMP2b, suggesting that overall, this is not a common cause of FTD (24). CHMP2B transcript is widely expressed, including throughout all brain regions. The yeast homologue of CHMP2B, Vps2, has been implicated in endosomal trafficking through the ESCRT (endosomal secretory complex required for trafficking) III complex. Expression of epitope-tagged mutant isoforms of CHMP2B in cell culture appeared to lead to aberrations in late endosomal trafficking.

A further link between ALS and FTD has been suggested by the finding of CHMP2B missense mutations in one patient with bulbar onset ALS and one patient with ALS–FTD, although the change in this latter patient was also found in a control sample, making its significance uncertain (25). In contrast to the FTD3 family, autopsy studies revealed ubiquitin pathology in the first, pure ALS case. Although this gene seems to be an uncommon cause of FTD, further elucidation of its function may give some insight into the mechanism of both FTD and ALS.


   DYNACTIN
TOP
 ABSTRACT
 INTRODUCTION
 FRONTOTEMPORAL DEMENTIA
 GENETIC LINKAGE STUDIES IN...
 CHMP2B
 DYNACTIN
VALSOLIN-CONTAINING PROTEIN
 PROGANULIN
 CONCLUSIONS
 REFERENCES
 
The dynactin multisubunit complex acts as an activator of dynein, the major retrograde transport motor for organelles, protein and RNA complexes in axons (26). Disruption of this system through mutations in dynein or components of the dynactin complex in mice results in a motor neuron degeneration phenotype (27,28). In 2003, a mutation in the p150 subunit of dynactin (DCTN1) was found in a family in which a highly unusual motor neuron disorder had been linked to 2p13 (29). The most common presenting symptom was stridor due to vocal cord weakness at ages ranging from 23 to 44. Bulbar involvement and facial weakness were eventually seen in all cases. Cognition was reported to be normal. Munch et al. (30) screened 250 ALS patients, of whom 108 had a family history, for mutations in dynein or p150-dynactin and identified three missense mutations in the latter. None of the patients was reported to have cognitive involvement, and the penetrance in one of the familial mutations appears to be low. The same group went on to describe a family in which FTD and ALS segregate as separate traits and in which each affected family member carried an R1101K mutation in dynactin (31). This would appear to represent yet another genetic mutation that may induce two separate neurodegeneration phenotypes. Whether ubiquitin pathology underlies the disease spectrum caused by DCTN1 mutations remains to be determined.


   VALSOLIN-CONTAINING PROTEIN
TOP
 ABSTRACT
 INTRODUCTION
 FRONTOTEMPORAL DEMENTIA
 GENETIC LINKAGE STUDIES IN...
 CHMP2B
 DYNACTIN
 VALSOLIN-CONTAINING PROTEIN
PROGANULIN
 CONCLUSIONS
 REFERENCES
 
Autosomal dominant inclusion body myopathy, Paget's disease of bone and frontotemporal dementia (FTD) occur together in a highly unusual disorder (MIM 605382 [OMIM] ) which mostly occurs in North America because of a founder effect. Linkage to 9p13.3–12 (32) led subsequently to the identification of mutations in the valsolin-containing protein (33). VCP is a member of the AAA-ATPase superfamily and has been implicated in a number of cellular functions including cell-cycle control, membrane fusion and the protein processing and degradation through the ubiquitin-proteasome pathway (34). Interestingly, post-mortem studies have confirmed that the FTD associated with VCP mutations is indeed a ubiquitinopathy (35) with widespread intranuclear ubiquitin inclusions in addition to the more classical cytoplasmic FTD-U pathology (36). Transfection of mutant VCP impairs degradation of ubiquitinated proteins normally handled by the ERAD (ER-associated degradation) pathway (37). Although this is a relatively uncommon disorder, its importance lies in providing a clear molecular link between a specific gene mutation and ubiquitin-associated neurodegeneration pathology.


   PROGANULIN
TOP
 ABSTRACT
 INTRODUCTION
 FRONTOTEMPORAL DEMENTIA
 GENETIC LINKAGE STUDIES IN...
 CHMP2B
 DYNACTIN
 VALSOLIN-CONTAINING PROTEIN
 PROGANULIN
CONCLUSIONS
 REFERENCES
 
The puzzling finding that FTD in a number of families demonstrated neither tau mutations nor tau pathology, yet mapped to chromosome 17q, has recently been explained by the identification of mutations in another gene adjacent to MAP-tau. Baker et al. (38) sequenced candidate genes in an ~6 Mb region defined by the linkage analysis and identified mutations in progranulin, which is located a mere 1.7 Mb upstream of MAP-tau. All of the mutations identified led to premature termination and a truncated mRNA that was subjected to nonsense-mediated decay. FTD related to progranulin is thus caused by haploinsuffiency. Similar findings were identified in Belgian patients with FTD-17U, including the observation that this cause of FTD is at least three times as common as FTDP-17T (39). Progranulin has a wide range of functions including in tissue response to injury. Excess progranulin promotes tumour formation and is therefore a cell survival signal, which presumably explains why reduction in levels promotes neurodegeneration. Interestingly, the neuropathology in patients with PGRN mutations consists yet again of ubiquitin-only cytoplasmic inclusions of FTD-U type combined with intranuclear pathology, reminiscent of that seen in some cases of FALS. Although clinical and pathological features of ALS were noted so far in only one patient with a confirmed PGRN mutation (40), progranulin is of potential relevance for the pathogenesis of motor neuron degeneration, as progranulin has been shown to stimulate VEGF expression (41). Given that VEGF has been implicated as a growth factor for motor neurons and polymorphisms in VEGF are associated with an increased risk of ALS in some populations (42), this provides a further potential link between FTD, ALS and ubiquitin pathology. Studies of the role of progranulin in ALS are awaited with interest.


   CONCLUSIONS
TOP
 ABSTRACT
 INTRODUCTION
 FRONTOTEMPORAL DEMENTIA
 GENETIC LINKAGE STUDIES IN...
 CHMP2B
 DYNACTIN
 VALSOLIN-CONTAINING PROTEIN
 PROGANULIN
 CONCLUSIONS
REFERENCES
 
There has been a growing body of clinical and pathological support for the notion that ALS and a form of FTD characterized by ‘ubiquitin-only’ pathology represent a disease continuum. Recent genetic studies provide support for this model. There appears to be a major disease locus for ALS–FTD on chromosome 9p; the identification of the causative mutation will be an important step in understanding the pathogenesis of both ALS and FTD and will hopefully go some way towards answering why too distinct clinical phenotypes can arise through a common genetic mechanism. Mutations in CHMP2B appear to be a rare cause of FTD, and there is provisional evidence for a role in ALS. Further analysis of the role of this gene through transgenic mouse models can be expected to contribute to our understanding of commoner forms of disease. The identification of mutations in the VCP gene provides a potentially important link between the ubiquitin–proteasome pathway and ubiquitin inclusion pathology. Even the genes that do not account for the majority of cases of FALS or FTD may turn out to play a more significant role than can be appreciated at present. In addition to providing general insights into the molecular pathogenesis of neurodegeneration, these genes are good candidates to form part of oligogenetic susceptibility profiles for ALS and FTD. Further screening of ALS/FTD populations and SNP haplotyping is therefore justified. The identification of progranulin mutations as the cause of FTD-17U opens up a new avenue of investigation and is potentially a major contribution to our understanding of neurodegeneration. The remarkable discovery that at least two of the newly described genetic causes of ALS/FTD (those associated with VCP and PGRN) are associated with an extension or shift of the usual cytoplasmic ubiquitin pathology of FTD-U into the nucleus must be pathogenetically relevant and is likely to lead to a refinement of FTD pathological criteria.

The conjunction of two neurodegeneration phenotypes within the same families and indeed within the same individuals raises some fascinating questions about the fundamental initiation of the disease process. What determines if a specific family member develops ALS or FTD is an important area for future work. The difference in phenotype may be due to genetic co-factors, environmental triggers or stochastic factors in disease initiation within particular focal populations of neurons. By analogy with ‘tauopathies’ (Alzheimer's disease, PSP and CBD) and ‘synucleinopathies’ (Parkinson's disease and multiple system atrophy), the common histopathological features of FTD and ALS, with ubiquitin-only positive intracellular inclusions, may lead to these disorders being reclassified as ‘ubiquitinopathies’—at least until the nature of the aggregated ubiquitinated proteins becomes clearer. Although the exact role of the ubuitin pathway as ‘cause or consequence’ in the pathogenesis of the neurodegeneration remains uncertain, the evidence for protein mishandling as a central theme in ALS and FTD is becoming ever more compelling.

Conflict of Interest statement. None declared.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 FRONTOTEMPORAL DEMENTIA
 GENETIC LINKAGE STUDIES IN...
 CHMP2B
 DYNACTIN
 VALSOLIN-CONTAINING PROTEIN
 PROGANULIN
 CONCLUSIONS
 REFERENCES
 

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