TDP-43 pathological inclusions are a hallmark characteristic of the majority of ALS cases, however the different types of TDP-43 positive inclusions and their relevance to disease are poorly understood [30
]. The presence of distinct morphologies of neuronal cytoplasmic TDP-43 inclusions has been noted in a number of reports [23
], including one which hypothesizes that development of the two most common inclusion types, round and filamentous, may be distinct and manifest separately [38
]. We observe that almost all TDP-43 pathology in ALS patients with ataxin 2 polyQ expansions is characterized by filamentous inclusions and a striking paucity of round dense inclusions. To further investigate the pathological features of ALS associated with ataxin 2 polyQ expansions it will be important to expand these analyses to include additional ALS cases. While there is much variability in the types of inclusions seen in a sampling of ALS cases, the group harboring ataxin 2 polyQ expansions shares a characteristic pathology that can be separated from cases without ataxin 2 expansions as a whole.
Some cases in the control ALS group are also characterized by the same TDP-43 pathology, and it perhaps makes sense that other unidentified genetic risk factors could culminate in the same pattern of pathology. This would also lead us to predict that the round dense inclusions of TDP-43 are formed via a different mechanism or under different cellular conditions (M.P.H. and A.D.G. manuscript in preparation). TDP-43 is an intrinsically aggregation-prone protein [26
]; perhaps then different alterations to TDP-43 or different cellular environments can influence its misfolding trajectories towards distinct morphologies (e.g. round or skein-like). This study represents a starting point and follow-up studies are required to extend and confirm these findings in additional ALS autopsy cases harboring ataxin 2 polyQ expansions and to further define the role of ataxin 2 in ALS pathogenesis.
A convergence of neuropathology and genetics has provided fundamental insight into human neurodegenerative diseases [17
]. Case in point: the neuropathology of frontotemporal lobar degeneration (FTLD). The subclassification of different types of FTLD based on neuropathological features (e.g. ubiquitin-positive, tau-positive, TDP-43-positive, FUS-positive, etc.) [9
] has proven tremendously valuable in understanding disease mechanisms and is supported by the genetic underpinnings of various FTLD subtypes [9
]. Therefore, a similar stratification of ALS cases based on genetics and neuropathology will hopefully provide additional insight into disease mechanisms. The notion that different genetic causes can result in the same clinical phenotype, but differing neuropathology, has previously been proposed. In ALS alone, pathology has been subtyped into at least 3 exclusive categories, including ALS cases with TDP-43 pathology, FUS pathology or SOD1 pathology [2
]. Furthermore, chromosome 9-linked ALS and FTD cases, which are caused by a hexanucleotide repeat expansion in the C9ORF72
gene, exhibit distinct pathological features [1
]. In the future it will be of interest to compare the morphology of TDP-43 inclusions, as we have here for ataxin 2 (e.g. skein vs. round morphology), in ALS patients with distinct underlying genetic characteristics (e.g. mutations in VCP
). In the limited number of C9ORF72
ALS cases that we examined here (n
=3) we did not observe any significant differences in skein vs. round TDP-43 inclusions compared to ALS cases without C9ORF72
mutations, although a larger follow-up study will be important.
It was recently reported that different mutations in the FUS gene might result in differences in FUS pathology as well as differences in clinical phenotype (i.e. disease severity) [33
]. This example underscores the idea that mutations within the same gene can produce distinct pathology, which is relevant to disease and may suggest different underlying pathogenic mechanisms. There are some recent examples in which TDP-43 pathology has been subtyped within ALS [18
] and it is commonly split into subtypes within the related disorder, FTLD [36
]. Ataxin 2 polyQ expanded cases are another example where TDP-43 pathology can be subtyped in ALS, whereby a distinct difference in TDP-43 inclusion morphology (i.e. absence of large round inclusions and presence of prominent skein-like filamentous inclusions) characterizes disease with different genetic underpinnings.