Alteration of protein folding and degradation in motor neuron diseases: Implications and protective functions of small heat shock proteins Serena Carra a,b , Valeria Crippa c,d , Paola Rusmini c,d , Alessandra Boncoraglio a,c , Melania Minoia a , Elisa Giorgetti c,d , Harm H. Kampinga a , Angelo Poletti c,d, * a Department of Cell Biology, University Medical Center of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands b Dipartimento di Scienze Biomediche, Universita’ degli Studi di Modena e Reggio Emilia, via G. Campi 287, 41125 Modena, Italy c Dipartimento di Endocrinologia, Fisiopatologia e Biologia Applicata (DEFIB), ‘‘Centro di Eccellenza per lo studio delle Malattie Neurodegenerative’’ (CEND), Universita’ degli Studi di Milano, via Balzaretti 9, 20133 Milano, Italy d InterUniversity Center on Neurodegenerative Diseases of the Universities of Florence, Rome, Genoa and Milan, Italy Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84 2. Motor neuron diseases: classification and general characteristics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84 3. Protein folding, molecular chaperones and protein degradation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85 3.1. Disturbances in protein folding and protein degradation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86 3.2. Alteration of protein folding in spinal and bulbar muscular atrophy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87 3.3. Alteration of protein folding in amyotrophic lateral sclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88 Progress in Neurobiology 97 (2012) 83–100 A R T I C L E I N F O Article history: Received 6 July 2011 Received in revised form 16 September 2011 Accepted 20 September 2011 Available online 29 September 2011 Keywords: Neurodegeneration Motor neuron diseases Spinal and bulbar muscular atrophy Amyotrophic lateral sclerosis Small heat shock proteins Autophagy HSPB8 Protein misfolding Protein aggregation SBMA ALS A B S T R A C T Motor neuron diseases (MNDs) are neurodegenerative disorders that specifically affect the survival and function of upper and/or lower motor neurons. Since motor neurons are responsible for the control of voluntary muscular movement, MNDs are characterized by muscle spasticity, weakness and atrophy. Different susceptibility genes associated with an increased risk to develop MNDs have been reported and several mutated genes have been linked to hereditary forms of MNDs. However, most cases of MNDs occur in sporadic forms and very little is known on their causes. Interestingly, several molecular mechanisms seem to participate in the progression of both the inherited and sporadic forms of MNDs. These include cytoskeleton organization, mitochondrial functions, DNA repair and RNA synthesis/ processing, vesicle trafficking, endolysosomal trafficking and fusion, as well as protein folding and protein degradation. In particular, accumulation of aggregate-prone proteins is a hallmark of MNDs, suggesting that the protein quality control system (molecular chaperones and the degradative systems: ubiquitin–proteasome-system and autophagy) are saturated or not sufficient to allow the clearance of these altered proteins. In this review we mainly focus on the MNDs associated with disturbances in protein folding and protein degradation and on the potential implication of a specific class of molecular chaperones, the small heat shock proteins (sHSPs/HSPBs), in motor neuron function and survival. How boosting of specific HSPBs may be a potential useful therapeutic approach in MNDs and how mutations in specific HSPBs can directly cause motor neuron degeneration is discussed. ß 2011 Elsevier Ltd. All rights reserved. Abbreviations: ALS, amyotrophic lateral sclerosis; AR, androgen receptor; ATG5, autophagy-related gene 5; Bag, Bcl-2 associated athanogene; CBP, CREB-binding protein; CMA, chaperone-mediated autophagy; CMT, Charcot-Marie-Tooth; DAO, D-amino acid oxidase; DCTN1, dynactin 1; dHMN, distal hereditary motor neuropathy; DHT, dihydrotestosterone; DRPLA, dentatorubral-pallidoluysian atrophy; fALS, familial amyotrophic lateral sclerosis; FTLD, frontotemporal dementia/frontotemporal lobar degeneration; FUS/TLS, protein fused in sarcoma/translocated in liposarcoma; GnRH, gonadotropin-releasing hormone; HD, Huntington’s disease; HDAC6, histone deacetylase 6; Hip, HSC70-interacting protein; HMN, hereditary motor neuropathy; Hop, Hsp-organising protein; HSPBs, small HSP family; HSPs, heat shock proteins; LAMP2A, lysosome- associated membrane protein 2A; LITAF/SIMPLE, lipopolysaccharide-induced tumor necrosis factor-alpha factor/small integral membrane protein of lysosome/late endosome; MAP1-LC3, microtubule-associated protein light chain 3; MKBP, myotonic dystro-phy kinase-bind-protein; MND, motor neuron diseases; NEDD8, neural precursor cell expressed developmentally downregulated 8; NEFL, neurofilament light chain gene; NF, neurofilament; OPTN, optineurin; polyQ, elongated polyglutamine; sALS, sporadic amyotrophic lateral sclerosis; SBMA, spinal and bulbar muscular atrophy; SCA, spinocerebellar ataxia; SOD1, Cu/Zn superoxide dismutase; SQSTM1, sequestosome1; SRC-1, steroid receptor coactivator 1; TDP-43, TAR DNA-binding domain protein; UBQLN2, ubiquitin-like protein ubiquilin 2; UPS, ubiquitin–proteasome system. * Corresponding author at: Dipartimento di Endocrinologia, Fisiopatologia e Biologia Applicata, via Balzaretti 9, 20133 Milano, Italy. Tel.: +39 02 5031 8215; fax: +39 02 5031 8204. E-mail address: angelo.poletti@unimi.it (A. Poletti). Contents lists available at SciVerse ScienceDirect Progress in Neurobiology jo u rn al ho m epag e: ww w.els evier .c om /lo cat e/pn eu ro b io 0301-0082/$ – see front matter ß 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.pneurobio.2011.09.009