Mutant HSPB8 causes motor neuron-specific neurite degeneration

被引:74
作者
Irobi, Joy [3 ]
Almeida-Souza, Leonardo [3 ]
Asselbergh, Bob [3 ]
De Winter, Vicky [3 ]
Goethals, Sofie [3 ]
Dierick, Ines [3 ]
Krishnan, Jyothsna [4 ]
Timmermans, Jean-Pierre [5 ]
Robberecht, Wim [4 ]
De Jonghe, Peter [2 ,3 ,6 ]
Van den Bosch, Ludo [4 ]
Janssens, Sophie [3 ]
Timmerman, Vincent [1 ,3 ]
机构
[1] Univ Antwerp VIB, CDE, Dept Mol Genet, Peripheral Neuropathy Grp, B-2610 Antwerp, Belgium
[2] Univ Antwerp VIB, Dept Mol Genet, Neurogenet Grp, B-2610 Antwerp, Belgium
[3] Univ Antwerp, Inst Born Bunge, Neurogenet Lab, B-2020 Antwerp, Belgium
[4] Catholic Univ Louvain VIB, Vesalius Res Ctr, Lab Neurobiol & Expt Neurol, B-3000 Louvain, Belgium
[5] Univ Antwerp, Dept Vet Sci, Cell Biol & Histol Lab, B-2020 Antwerp, Belgium
[6] Univ Antwerp Hosp, Div Neurol, Antwerp, Belgium
关键词
MARIE-TOOTH-DISEASE; AMYLOID PRECURSOR PROTEIN; HEAT-SHOCK PROTEINS; AXON DEGENERATION; NEUROPATHY; DOMINANT; MECHANISMS; MUTATIONS; PROGRESSION; APOPTOSIS;
D O I
10.1093/hmg/ddq234
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Missense mutations (K141N and K141E) in the alpha-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.
引用
收藏
页码:3254 / 3265
页数:12
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