Molecular Biology of Small Heat Shock Proteins associated with Peripheral Neuropathies

Abstract

Heat‐shock proteins (HSPs) are molecular chaperones that protect the cell from various types of stress. Although regulated by stress, some of these proteins are constitutively expressed and responsible for quality control and protein folding. Based on their molecular weight, the HSP family mainly consists of two groups: large and small HSPs. The large HSPs require adenosine triphosphate (ATP) for their functioning, whereas the small HSPs (HSPBs) are ATP independent. The latter bind improperly folded proteins and assist in the targeting process for refolding or degradation. These HSPBs are not only molecular chaperones but they are also involved in many essential cellular processes such as apoptosis, autophagy, splicing, cytoskeleton dynamics and neuronal survival. This review focusses on the small HSPs HSPB1, HSPB3 and HSPB8, as mutations in these proteins are causative for Charcot–Marie–Tooth (CMT) disease and distal hereditary motor neuropathies (dHMN). Moreover, this review discusses the functional consequences of these mutations and their role in the length‐dependent neurodegeneration typical of CMT diseases. Key Concepts: The molecular signature of the small HSPs is the conserved α‐crystallin domain. Mutations in HSPB1, HSPB3 and HSPB8 are associated with dHMN and CMT subtypes. Mutant HSPB1 causes instability of the cytoskeletal elements and therefore disorganisation of the neuronal cytoskeleton could underlie the peripheral neuropathies. Mutant HSPB8 may induce pathomechanisms leading to CMT diseases through a loss of autophagy function, rather than a toxic gain of function. The HSPB3 protein differs considerably from the other members regarding sequence similarity such as the poor conservation in the N ‐terminal region and the very short C ‐terminal domain. It remains fragmentary how mutations in these small HSPs initiate a molecular cascade leading to progressive axonal degeneration.

Genetics of Charcot-Marie-Tooth (CMT) Disease within the Frame of the Human Genome Project Success

“…Screening for HSPB1 mutations in additional CMT and HMN families confirmed the previously observed mutation and identified several additional missense mutations [ 71 ]. Both small heat shock proteins act as molecular chaperones but are also involved in many essential cellular processes such as apoptosis, autophagy, splicing, cytoskeleton dynamics, and neuronal survival (reviewed by [ 72 ]). Transgenic mouse models for mutant HSPB1 have been created, which develop neurological symptoms similar to the human condition.…”

Neuropathy-causing mutations in HSPB1 impair autophagy by disturbing the formation of SQSTM1/p62 bodies

“…Mutations in HSPB1 lead to axonal Charcot-Marie-Tooth neuropathies (CMT2), distal hereditary motor neuropathy (dHMN) [4,5], and sporadic amyotrophic lateral sclerosis (ALS) [6]. The majority of disease-causing mutations in HSPB1 occur in the evolutionarily conserved α-crystallin domain (ACD) which is important for its oligomerization and interaction with other small heat shock proteins [7], but some mutations do exist in the N-or C-termini [8]. Functional analysis of the different reported mutations show that the location of the mutation can affect different functions of the protein [9].…”

Animal models and therapeutic prospects for Charcot–Marie–Tooth disease

“…[50][51][52] The HSPB1 gene is associated with 17 CMT-causing mutations. 50,51,[53][54][55][56] Nine of these mutations are located in the a-crystallin domain, which is conserved among the sHSP family and is essential for the formation of large oligomers. Mutations located inside or outside the acrystallin domain have different effects on the protein and result in different pathomechanisms.…”

“…Three members of the small heat shock family have been associated with CMT: HSPB1, HSPB3, and HSPB8 . The HSPB1 gene is associated with 17 CMT‐causing mutations . Nine of these mutations are located in the α‐crystallin domain, which is conserved among the sHSP family and is essential for the formation of large oligomers.…”

“…44 The latter represents the first attempt of therapeutic strategy for CMT2. 50,51,[53][54][55][56] Nine of these mutations are located in the a-crystallin domain, which is conserved among the sHSP family and is essential for the formation of large oligomers. Remarkably, this conditional expression is sufficient to elicit a phenotype resembling CMT.…”