Tale of two diseases: Amyotrophic lateral sclerosis and frontotemporal dementia
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.141174
Source of Support: None, Conflict of Interest: None
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) were independently described in clinical and pathological details more than a century ago. Recent breakthrough discoveries identifying common genes that are causal to either ALS or FTD or an overlapping ALS-FTD syndrome have dramatically transformed our view regarding their pathogenesis. Most recently, a massive hexanucleotide (GGGGCC) repeat expansion mutation in C9orf72 gene has been linked to the majority of familial ALS, FTD and mixed ALS-FTD cases. C9orf72 and other genes causal to ALS and FTD are consistently associated with the formation of cellular RNA inclusions and protein aggregates. This article summarizes the recently reported ALS-FTD-linked genes and the emerging common unifying mechanism in the pathogenesis of ALS-FTD spectrum disorders along with a comment on the potential new therapeutic targets in these hitherto incurable diseases.
Keywords: Amyotrophic lateral sclerosis, C9orf72, frontotemporal dementia, Protein aggregates, TAR DNA binding protein-43
In a series of case demonstrations, lectures and publications in 1860s, Jean-Martin Charcot of La Salpêtrière hospital in Paris described the clinicopathological entity of progressive muscular atrophy (amyotrophy) and pyramidal tract degeneration (lateral sclerosis), and named it amyotrophic lateral sclerosis (ALS), also called Charcot's disease or motor neuron disease.  Thirty years later in 1892, Arnold Pick, a psychiatrist at the Viennese hospital in Prague, published a case report under the title 'on the relationship between senile cerebral atrophy and aphasia', describing specifically behavioral symptoms and speech difficulty in conjunction with gross frontotemporal lobe atrophy.  Familiar with Carl Wernicke's opinion (with whom Pick had previously worked in Berlin) that 'General Paralysis of the Insane' can be associated with focal neuropsychological deficits, Pick affirmed his thesis that prominent neuropsychiatric symptoms could emanate also from focal cerebral atrophy in senile dementia. What particularly drew Pick's attention in his case, in addition to dementia, was the unusually severe language disorder, now widely recognized as the first description of primary progressive aphasia (PPA).  Pick did not perform microscopic study in this and other cases that he his colleagues subsequently reported. ,
In 1911, Alois Alzheimer described the pathological findings in patients with frontotemporal lobe degeneration (FTLD),  specifically pointing the absence of senile plaques and neurofibrillary tangles that he had described in a disease in 1907 that bears his name. Alzheimer reported instead the presence of argyrophilic neural inclusions and swollen cells in FTLD, later called Pick bodies and Pick cells, respectively.  Although motor cortex (pyramidal tracts) can be potentially involved in FTLD, a clear connection between frontotemporal dementia (FTD) and ALS remained unknown for almost a century.
Two major research groups from Lund in Sweden and Manchester in England  in 1990s proposed clinic and neuropathological criteria of FTD which later Neary et al.,  in 1998 refined as consensus diagnostic criteria of FTLD in the American Academy of Neurology practice guidelines. FTLD is characterized by progressive atrophy with neuronal loss in the frontal and temporal cortices and is characterized clinically by behavior changes (bvFTD) as well as gradual impairment of language skills, PPA. PPA phenotype of FTLD is further subclassified into three subtypes: The common nonfluent variant (nfvPPA) and rare logopenic (lvPPA) and semantic dementia (sdvPPA) variants.  FTD is the second most common cause of degenerative dementia after Alzheimer's disease. ,,
As the clinical FTD syndrome became widely recognized, it also became evident in ALS community that bvFTD was particularly common in ALS. Up to half of ALS patients have cognitive behavioral or linguistic impairment attributable to FTLD. ,, Recent discovery of mutation in chromosome 9 open reading frame 72 (C9orf72) as a major cause of familial ALS, FTD and mixed ALS-FTD syndrome closes the clear relationship between ALS and FTD and provides new insight in the pathogenesis of these related disorders. ,
Convergence of genetic causes of ALS and FTD
Similar in clinical details, familial (10%) and sporadic (90%) ALS (familiarly known as Lou Gehrig's disease in the United States) is characterized by premature degeneration of upper and lower motor neurons. ALS is a progressive disease and patients with ALS generally survive 3-5 years after the disease-onset. Mutations in four genes (C9orf72, SOD1, TDP-43, and FUS) account for approximately 65% of the familial ALS cases. ,,,,, Other rare genes causal to familial ALS include microtubule-associated protein tau (MAPT),  progranulin (PGRN),  valosin containing protein (VCP),  ubiquilin2 (UBQLN2),  and charged multivesicular protein 2B (CHMP2B). 
Clinically indistinguishable, familial (50%) and sporadic FTD is characterized by progressive loss of neuronal cells in frontal and temporal lobes. The typical clinical picture in FTD and Pick's FTLD is a slowly progressive dementia dominated at early stage by prominent personality and behavior changes,  lack of insight, disinhibition, and at later stage by psychomotor slowing, stereotype and apathy. , There can also be progressive impairment of speech, often ending in mutism. Memory and visuospatial functions are generally spared, although elements of Klûver-Bucy syndrome (blunt affect, hyperorality and hypersexuality, likely from the medial frontal and temporal lobe degeneration) can be other recognizable features in FTD.  Mutations in first two identified causal genes encoding the MAPT and PGRN account for 10%-20% of familial FTD [Table 1]. Mutations in TDP-43, FUS, UBQLN2, VCP and CHMP2B are causal for a small proportion of familial FTD. Most recently, hexanucleotide (GGGGCC, G 4 C 2 ) expansion mutation in C9orf72 gene is linked to most genetic as well as some sporadic forms of FTD ,,,, [Table 1].
Although MAPT- and PGRN-gene-associated FTD were reported on occasion to show ALS features, the real breakthrough linking ALS and FTD disease mechanisms came with the identification of TDP-43 as the major ubiquitinated protein in both sporadic and non-SOD1 familial ALS and in most pathological forms of FTD. , This finding was followed soon thereafter by the discovery of mutations in the gene encoding the TDP-43 in patients with ALS as well as FTD.  Recognition that mutation in RNA-binding protein (TDP-43) was causal to ALS and FTD was quickly expanded to screen for other RNA binding proteins. Mutations in the FUS gene (another RNA binding protein) are now shown to account for an additional 5% of familial ALS and some cases of FTD.  Recently, the most convincing direct molecular link between ALS and FTD has been the identification of a large intronic hexanucleotide expansion (few hundreds to thousands of G 4 C 2 repeats) in the previously uncharacterized C9orf72 gene of unknown function in families with ALS, FTD, and overlapping ALS-FTD syndrome. ,,,,
Hexanucleotide G 4 C 2 expansion in C9orf72 gene accounts for approximately 40% of familial ALS, 10% of sporadic ALS, 5% of sporadic FTD, and up to 80% of familial ALS-FTD cases, and thus, it makes G 4 C 2 repeat expansion the most common cause of ALS and FTD. ,,,, Since its discovery in November 2011, approximately 3400 cases of C9orf72 expansion have been reported in the medical literature, with over 75,000 case and control samples screened. Over 95% of these expansions are associated with a clinical phenotype of ALS, bvFTD or a combined syndrome of ALS and bvFTD. Frequencies of familial and sporadic C9orf72 expansion-associated ALS and FTD are remarkably high in Finland and some other specific European populations, indicating a founder effect.  There is a normal variation in the number of non-expanded G 4 C 2 repeats in the population, with controls commonly possessing 2, 5, or 8 repeats on each allele or on the non-expanded allele in patients who are heterozygous for the expansion. Expansions greater than 400 repeats confer disease risk in a dominant fashion. A panoply of clinical ALS phenotypes, including classical ALS, progressive muscular atrophy and primary lateral sclerosis, is linked to G 4 C 2 expansion, but generally expansion-associated ALS is more often bulbar-onset, it shows cognitive impairment at relatively earlier age, and it follows an accelerated disease progression compared with patients without expansion. 
Thus, ALS and FTD are linked genetically, clinically, and pathologically, and both these diseases should now be properly recognized as representative of a continuum of a broad neurodegenerative disorder, with each presenting a spectrum of overlapping clinical phenotypes. More recent insight that the products of these identified genes are involved in RNA metabolism and protein homeostasis provides a further mechanistic link in the pathogenesis of ALS/FTD spectrum disorders.
Errors in RNA metabolism and proteostasis in ALS and FTD
During the last few years, based on convincing research data, a provocative theme has emerged that autosomal-dominant genes that primarily cause ALS or FTD are involved in different stages of RNA processing and metabolism , (see review  ). These genes include TDP-43, FUS, C9orf72, and others [Table 1]. Additionally, mutations in at least two genes-UBQLN2 and VCP can also give rise to ALS and/or FTD along with TDP-43 positive neuropathology. , UBQLN2 is one of the families of proteins involved in targeting abnormal proteins for degradation via lysosomal and proteosomal degradation pathways.  VCP is thought to be important in degradation of larger subcellular structures via autophagy rout.  Thus, errors in RNA metabolism as well as in protein turnover and clearance seem to be the key unifying pathogenic mechanism in ALS/FTD spectrum disorders.
TDP-43 was first identified as a protein that binds to the trans-activation response (TAR) element of human immunodeficiency virus and was named TAR DNA-binding protein (of 43 kD molecular weight). TDP-43 mutations are mostly clustered in the glycine-rich domain and mutated TDP-43 or its products are prone to protein-aggregate formation. ,,, ALS/FTD-linked FUS mutations are generally clustered in the C-terminal nuclear localization signal (NLS) domain.  TDP-43 and FUS can bind to single- or double-stranded DNA, as well as RNA, and they participate in an array of RNA transcription, splicing and their cytosolic metabolism (see review , ). TDP-43 and FUS shuttle from the nucleus to the cytosol, where they have been associated with cytoplasmic RNA granules.  These granules include processing bodies (P bodies), which contain RNA granules to be locally translated as well as stress granules, which are presumably RNA decay machineries.
In recent years, multiple transgenic approaches have been employed to identify properties of mutant TDP-43 and FUS. Consensus is now emerging on two key factors in TDP-43 and FUS-linked ALS-FTD disorders. ,, First, Loss of nuclear function of TDP-43 and FUS is a component of disease process, as nuclear clearing accompanied by its cytoplasmic accumulation has been a universal feature in surviving neurons in these transgenic models. It is however unclear if nuclear clearance, cytoplasmic accumulation, or both play roles in TDP-43- and FUS-linked diseases. But, this observation coupled with the evidence that mutant TDP-43 and FUS associate with stress granules in ALS and FTD cases sets the stage for investigators to focus on what the relationship is between this process and the nuclear clearance of TDP-43 and FUS, how TDP-43 and FUS switch from reversible association into irreversible pathogenic inclusions and possible therapeutic targets to reverse the pathogenic process.
Second, an increasing body of evidence has established that cell types beyond the target neurons whose dysfunction is responsible for the primary phenotypes of ALS and FTD also contribute to neurodegeneration, a phenomenon known as 'non-cell-autonomous' toxicity. This phenomenon explains focal initiation and regional spread of the disease process in ALS-FID spectrum disorders. ,
The expanded G 4 C 2 hexanucleotide repeat in the C9orf72 gene is reminiscent of multiple prior repeat expansion diseases for which three different prototypes of pathogenic mechanisms have been demonstrated: ,, Loss of function of the gene containing the repeat (haploinsufficiency), toxic gain of property due to the expression of protein containing the repeat expansion (mutant protein), and the gain of RNA toxicity due to the production of RNA containing the G 4 C 2 repeat expansion (mutant RNA). Toxicity of repeat expansion-associated non-ATG translation (RAN) products is also shown to account for cellular toxicity in C9orf72 mutation. ,
Although some cause-and-effect question persists for whether protein aggregation per se causes or merely reflects a consequence of neurodegenerative diseases, overwhelming evidence supports protein aggregates as the proximate cause of cellular toxicity. Proteins are continuously formed, degraded and recycled in living cells. It is also now known that degradation deficits through disruption of either of the two major protein clearance pathways-the ubiquitin-proteasome system and autophagy- can be causal of ALS and FTD ,, [Table 1]. Taken together, converging pathogenic mechanisms underlying ALS and FTD appear to be the disruption of RNA processing and protein homeostasis that drives disease initiation and progression. Although the initial event that triggers disease initiation is unknown, it could be at multiple points in RNA or protein homeostasis pathways, including genetic mutations that predispose one pathway to be more error prone or other nongenetic factor, such as environmental factor or aging that may tip the balance to proteostasis decline.
Jean-Martin Charcot (1825-1893) and Arnold Pick (1851-1924) provided the first descriptions of the neurodegenerative diseases associated with their names, but the importance of these diseases in neuroscience goes far beyond their eponymic gifts. With recent advances in identifying common genetic causes and the identities of major components of the cellular aggregates in ALS and FTD, disruption of RNA metabolism and protein homeostasis seems to be the unifying central pathogenic mechanism in these neurodegenerative disorders. With expanding knowledge of genetic causes and molecular mechanisms, it is an exciting time for discoveries in ALS and FTD. Much remains still to be explored, however, including prospects for therapies designed towards lowering synthesis of toxic RNA and protein species and improving protein homeostasis. Fueled by ground-breaking recent discoveries and increasing pace of research in these currently incurable disorders, it is worth recalling Charcot's comments over 145 years ago, 'the prognosis, up to the present, is of the gloomiest.……the verdict we will give such a patient tomorrow will not be the same we must give this man today'.