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Please use this identifier to cite or link to this item: http://hdl.handle.net/1942/24223

Title: A knock-in/knock-out mouse model of HSPB8-associated distal hereditary motor neuropathy and myopathy reveals toxic gain-of-function of mutant Hspb8
Authors: Bouhy, Delphine
Juneja, Manisha
Katona, Istvan
Holmgren, Anne
Asselbergh, Bob
De Winter, Vicky
Hochepied, Tino
Goossens, Steven
Haigh, Jody J.
Libert, Claude
Ceuterick-de Groote, Chantal
Irobi, Joy
Weis, Joachim
Timmerman, Vincent
Issue Date: 2017
Citation: ACTA NEUROPATHOLOGICA, 135 (1), p. 131-148
Status: Early View
Abstract: Mutations in the small heat shock protein B8 gene (HSPB8/HSP22) have been associated with distal hereditary motor neuropathy, Charcot–Marie–Tooth disease, and recently distal myopathy. It is so far not clear how mutant HSPB8 induces the neuronal and muscular phenotypes and if a common pathogenesis lies behind these diseases. Growing evidence points towards a role of HSPB8 in chaperone-associated autophagy, which has been shown to be a determinant for the clearance of poly-glutamine aggregates in neurodegenerative diseases but also for the maintenance of skeletal muscle myofibrils. To test this hypothesis and better dissect the pathomechanism of mutant HSPB8, we generated a new transgenic mouse model leading to the expression of the mutant protein (knock-in lines) or the loss-of-function (functional knock-out lines) of the endogenous protein Hspb8. While the homozygous knock-in mice developed motor deficits associated with degeneration of peripheral nerves and severe muscle atrophy corroborating patient data, homozygous knock-out mice had locomotor performances equivalent to those of wild-type animals. The distal skeletal muscles of the post-symptomatic homozygous knock-in displayed Z-disk disorganisation, granulofilamentous material accumulation along with Hspb8, αB-crystallin (HSPB5/CRYAB), and desmin aggregates. The presence of the aggregates correlated with reduced markers of effective autophagy. The sciatic nerve of the homozygous knock-in mice was characterized by low autophagy potential in pre-symptomatic and Hspb8 aggregates in post-symptomatic animals. On the other hand, the sciatic nerve of the homozygous knock-out mice presented a normal morphology and their distal muscle displayed accumulation of abnormal mitochondria but intact myofiber and Z-line organisation. Our data, therefore, suggest that toxic gain-of-function of mutant Hspb8 aggregates is a major contributor to the peripheral neuropathy and the myopathy. In addition, mutant Hspb8 induces impairments in autophagy that may aggravate the phenotype.
Notes: Timmerman, V (reprint author), Univ Antwerp, Dept Biomed Sci, Peripheral Neuropathy Res Grp, Univ Pl 1, B-2610 Antwerp, Belgium. vincent.timmerman@uantwerpen.be
URI: http://hdl.handle.net/1942/24223
DOI: 10.1007/s00401-017-1756-0
ISI #: 000419470000009
ISSN: 0001-6322
Category: A1
Type: Journal Contribution
Appears in Collections: Research publications

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