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Missense mutations (K141N and K141E) in the α-crystallin domain of the small heat shock protein HSPB8 (HSP22) cause distal hereditary motor neuropathy (distal HMN) or Charcot-Marie-Tooth neuropathy type 2L (CMT2L). The mechanism through which mutant HSPB8 leads to a specific motor neuron disease phenotype is currently unknown. To address this question, we compared the effect of mutant HSPB8 in primary neuronal and glial cell cultures. In motor neurons, expression of both HSPB8 K141N and K141E mutations clearly resulted in neurite degeneration, as manifested by a reduction in number of neurites per cell, as well as in a reduction in average length of the neurites. Furthermore, expression of the K141E (and to a lesser extent, K141N) mutation also induced spheroids in the neurites. We did not detect any signs of apoptosis in motor neurons, showing that mutant HSPB8 resulted in neurite degeneration without inducing neuronal death. While overt in motor neurons, these phenotypes were only very mildly present in sensory neurons and completely absent in cortical neurons. Also glial cells did not show an altered phenotype upon expression of mutant HSPB8. These findings show that despite the ubiquitous presence of HSPB8, only motor neurons appear to be affected by the K141N and K141E mutations which explain the predominant motor neuron phenotype in distal HMN and CMT2L.

Amyotrophic lateral sclerosis (ALS) is a chronic, adult‐onset neurodegenerative disorder characterized by the selective loss of upper and lower motor neurons, resulting in severe atrophy of muscles and death. Although the exact pathogenic mechanism of mutant superoxide dismutase 1 (SOD1) causing familial ALS is still elusive, toxic protein aggregation leading to insufficiency of chaperones is one of the main hypotheses. In this study, we investigated the effect of over‐expressing one of these chaperones, heat shock protein 27 (Hsp27), in ALS. Mice over‐expressing the human, mutant SOD1G93A were crossed with mice that ubiquitously over‐expressed human Hsp27. Even though the single transgenic hHsp27 mice showed protection against spinal cord ischemia, the double transgenic SOD1G93A/hHsp27 mice did not live longer, and did not show a significant delay in the onset of disease compared to their SOD1G93A littermates. There was no protective effect of hHsp27 over‐expression on the motor neurons and on the mutant SOD1 aggregates in the double transgenic SOD1G93A/hHsp27 mice. In conclusion, despite the protective action against acute motor neuron injury, Hsp27 alone is not sufficient to protect against the chronic motor neuron injury due to the presence of mutant SOD1.

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Small heat-shock proteins (small Hsps) are a family of highly conserved proteins involved in multiple cellular mechanisms. Apart from their central role as chaperones in protecting cells during stressful conditions (as outlined in the previous two chapters), small Hsps also function to maintain cellular homeostasis in physiological conditions. Correct protein refolding to avoid aggregation, targeting misfolded proteins for degradation, proper cytoskeletal organization, and anti-apoptotic functions are some of the extensively studied attributes of small Hsps. One or more of these cellular mechanisms may malfunction in specific sets of neurons leading to neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, polyglutamine disorders, and amyotrophic lateral sclerosis. Many in vitro models of these diseases have demonstrated the beneficial roles of small Hsps pointing out their protective role in attenuating the neurodegenerative phenotype. Interestingly, mutations in small Hsps themselves were linked to other degenerative disorders like inherited peripheral neuropathies and familial myopathies. Although not much is known regarding the exact patho-mechanism ("loss of function" or "gain of function") of mutations in causing disease, these discoveries reiterate the importance of small Hsps in maintaining neuronal health and indicate that the small Hsp family of proteins might have more functions than meets the eye. This chapter reviews the current knowledge regarding these enigmatic proteins, including their structure and function and how mutations in these once "forgotten proteins" might alter their functions and cause neurodegeneration.