The Small Heat-Shock Proteins: Cellular Functions and Mutations Causing Neurodegeneration

Abstract

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.

Axonal Charcot–Marie–Tooth disease

“…Most of the CMT causing mutations are within the a-crystallin domain [66,67], which is necessary for many of the Hsp functions [68 ]. Clinical phenotypes have been variable with most patients presenting with distal weakness of lower and upper limbs, length-dependent sensory loss, decreased reflexes and foot deformities [68 ]. Scoliosis, vocal cord paresis, glaucoma, and cranial nerve involvement have been reported [23].…”

“…Inheritance in autosomal dominant and autosomal recessive patterns has been described [22]. These proteins are among the 8-member human small Hsp superfamily (reviewed in [68 ]). The Hsp members are related to lens crystallins and have a conserved a-crystallin domain that is between an N-terminal domain containing a hydrophobic WDPF motif (W ¼ tryptophan, D ¼ aspartic acid, P ¼ proline, F ¼ phenylalanine) and a variable Axonal Charcot-Marie-Tooth disease Shy and Patzkó 479 C-terminal tail that contains an IXI/V motif.…”

“…Multiple pathogenic mechanisms are possible and being investigated for these disorders based in part on the multiple actions of the Hsps. These potential mechanisms include impaired chaperon activity, formation of aggregates that sometimes may involve neurofilaments, disruption of the cytoskeleton and axonal transport, disrupted interactions with other Hsp members, and predisposition to apoptosis and autophagy (see [68 ]). …”

“…The Hsp members are related to lens crystallins and have a conserved a-crystallin domain that is between an N-terminal domain containing a hydrophobic WDPF motif (W ¼ tryptophan, D ¼ aspartic acid, P ¼ proline, F ¼ phenylalanine) and a variable Axonal Charcot-Marie-Tooth disease Shy and Patzkó 479 C-terminal tail that contains an IXI/V motif. Most of the CMT causing mutations are within the a-crystallin domain [66,67], which is necessary for many of the Hsp functions [68 ]. Clinical phenotypes have been variable with most patients presenting with distal weakness of lower and upper limbs, length-dependent sensory loss, decreased reflexes and foot deformities [68 ].…”