Selective vulnerability in frontotemporal dementia and amyotrophic lateral sclerosis
The anatomy of neurodegenerative disease can be understood in terms of two key aspects: onset and progression. Whereas mechanisms of progression have become clearer in recent years, factors controlling neuron type-specific onset remain mysterious. These mysteries become intertwined when considering a disease like the TDP-43 proteinopathy linked to amyotrophic lateral sclerosis and frontotemporal dementia, in which onset may occur within the pyramidal motor system, the social-emotional system, or both.
In the pyramidal motor system, corticospinal motor neurons reside in Layer 5b of the primary motor cortex, express transcription factors CTIP2 and FEZF2, and project large, long-range axons to the spinal cord anterior horn. In the social-emotional system, von Economo neurons (VENs) reside in Layer 5b of the anterior cingulate and frontoinsular cortex, regions that may represent the major efferent and afferent representations of the viscero-autonomic-emotional system. VENs also express CTIP2 and FEZF2, suggesting that they are long-range subcerebral projection neurons, perhaps with connections to brainstem autonomic integration centers or even spinal cord. Shared vulnerability among these neuron pools could explain the association between bvFTD and ALS, but mechanisms underlying this shared vulnerability remain unknown. Nonetheless, a focus on these selectively vulnerable neurons has begun to reveal key aspects of disease pathogenesis. In this lecture, I will discuss this emerging literature, with special attention to TDP-43 loss of function and toxicity and the special role of expansions in C9orf72.