title: Sensory neuropathy attributable to loss of Bcl-w.
abstract: Small fiber sensory neuropathy is a common disorder in which progressive degeneration of small-diameter nociceptors causes decreased sensitivity to thermal stimuli and painful sensations in the extremities. In the majority of patients, the cause of small fiber sensory neuropathy is unknown, and treatment options are limited. Here, we show that Bcl-w (Bcl-2l2) is required for the viability of small fiber nociceptive sensory neurons. Bcl-w(-/-) mice demonstrate an adult-onset progressive decline in thermosensation and a decrease in nociceptor innervation of the epidermis. This denervation occurs without cell body loss, indicating that lack of Bcl-w results in a primary axonopathy. Consistent with this phenotype, we show that Bcl-w, in contrast to the closely related Bcl-2 and Bcl-xL, is enriched in axons of sensory neurons and that Bcl-w prevents the dying back of axons. Bcl-w(-/-) sensory neurons exhibit mitochondrial abnormalities, including alterations in axonal mitochondrial size, axonal mitochondrial membrane potential, and cellular ATP levels. Collectively, these data establish bcl-w(-/-) mice as an animal model of small fiber sensory neuropathy and provide new insight regarding the role of Bcl-w and of mitochondria in preventing axonal degeneration.
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Courchesne
authors.forename: Christoph
authors.initials: C
authors.lastname: Karch
authors.forename: Maria F
authors.initials: MF
authors.lastname: Pazyra-Murphy
authors.forename: Rosalind A
authors.initials: RA
authors.lastname: Segal
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D001369:Axons / Q000473:pathology*; D001522:Behavior, Animal; D015153:Blotting, Western; D002452:Cell Count; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004817:Epidermis / Q000294:innervation*; D005260:Female; D005727:Ganglia, Spinal / Q000166:cytology; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D009412:Nerve Fibers / Q000473:pathology; D009483:Neuropsychological Tests; D009619:Nociceptors / Q000378:metabolism*; D010523:Peripheral Nervous System Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011247:Pregnancy; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012684:Sensory Thresholds; D013697:Thermosensing / Q000235:genetics*
chemical_list: D051017:Apoptosis Regulatory Proteins; C101155:Bcl2l2 protein, mouse; D011506:Proteins; D000255:Adenosine Triphosphate