Toward Elucidating Neuronal Subtype-Specific Subcellular Vulnerability in ALS
This talk will discuss two central ideas relevant to ALS, both dealing with circuit development, synaptic maintenance, and selective vulnerability of the “upper motor neurons” involved: 1) that distinct and subcellularly localized molecular machinery of corticospinal motor neurons (CSMN) and their related subsets of subcerebral projection neurons (SCPN), and potentially shared molecular components or pathways with spinal motor neurons (SMN), underlie the selective and specific vulnerability of these circuit partners among all the other thousands of relatively unaffected neuronal populations; and 2) that even subtle abnormalities in the development, synaptic maintenance, and subcellular molecular machinery of CSMN / SCPN (and SMN, for that matter) might both be explained by specific functions of many/most of the known ALS vulnerability genes, and predispose these specific cortical neuron populations to vulnerability and later neurodegeneration in ALS / MND.
Given the immense diversity of CNS neuronal subtypes (cortical projection neurons in particular), and the complexity of their connections, complex and subtype-specific subcellular molecular machinery (in particular, in growth cones during circuit development, which mature into diverse and potentially quite subtype-specific forms of synapses) regulate differentiation, circuit connectivity, synapse function, and ultimately survival. This subcellular and subtype- / stage-specific in vivo molecular machinery was previously experimentally inaccessible.
We recently developed experimental and analytic approaches to deeply investigate subtype- and stage-specific subcellular RNA and protein molecular machinery directly in vivo in mice (and very recently with human neurons), in particular in growth cones vs. their own parent somata (Poulopoulos*, Murphy*, Nature, 2019). We have discovered a number of novel and in some cases non-canonical modes of subtype-specific subcellular RNA processing, localization, and utilization, functions of a number of ALS vulnerability genes. During circuit development and function, even very subtle errors might be introduced that anticipate later degeneration of specifically vulnerable neuronal populations. I will discuss our initial work on these issues.