The heat shock response in neurons and astroglia and its role in neurodegenerative diseases

Protein inclusions are a predominant molecular pathologyfound in numerous neurodegenerative diseases, including amyotrophic lateral sclerosisand Huntington’s disease. Protein inclusions form in discrete areas of the brain characteristic to the type of neurodegenerative disease, and coincide with the death of neurons in that region (e.g. spinal cord motor neurons in amyotrophic lateral sclerosis). This suggests that the process of protein misfolding leading to inclusion formation is neurotoxic, and that cell-autonomous and non-cell autonomous mechanisms that maintain protein homeostasis ( proteostasis) can, at times, be insufficient to prevent protein inclusion formation in the central nervous system. The heat shockresponse is a pro-survival pathway induced under conditions of cellular stress that acts to maintain proteostasisthrough the up-regulation of heat shockproteins, a superfamily of molecular chaperones, other co-chaperonesand mitotic regulators. The kinetics and magnitude of the heat shockresponse varies in a stress- and cell-type dependent manner. It remains to be determined if and/or how the heat shockresponse is activated in the different cell-types that comprise the central nervous system (e.g. neurons and astroglia) in response to protein misfolding events that precede cellular dysfunctions in neurodegenerative diseases. This is particularly relevant considering emerging evidence demonstrating the non-cell autonomous nature of amyotrophic lateral sclerosisand Huntington’s disease(and other neurodegenerative diseases) and the destructive role of astroglia in disease progression. This review highlights the complexity of heat shockresponse activation and addresses whether neurons and glia senseand respondto protein misfolding and aggregation associated with neurodegenerative diseases, in particular Huntington’s diseaseand amyotrophic lateral sclerosis, by inducing a pro-survival heat shockresponse.