The Vps33a gene regulates behavior and cerebellar Purkinje cell number.
A mutation in the Vps33a gene causes Hermansky-Pudlak Syndrome (HPS)-like-symptoms in the buff (bf) mouse mutant. The encoded product, Vps33a, is a member of the Sec1 and Class C multi-protein complex that regulates vesicle trafficking to specialized lysosome-related organelles. As Sec1 signaling pathways have been implicated in pre-synaptic function, we examined brain size, cerebellar cell number and the behavioral phenotype of bf mutants. Standardized behavioral tests (SHIRPA protocols) demonstrated significant motor deficits (e.g., grip strength, righting reflex and touch escape) in bf mutants, worsening with age. Histological examination of brain revealed significant Purkinje cell loss that was confirmed with staining for calbindin, a calcium binding protein enriched in Purkinje cells. This pathologic finding was progressive, as older bf mutants (13-14 months) showed a greater attrition of neurons, with their cerebella appearing to be particularly reduced (approximately 30%) in size relative to those of age-matched-control cohorts. These studies suggest that loss of Purkinje neurons is the most obvious neurological atrophy in the bf mutant, a structural change that generates motor coordination deficits and impaired postural phenotypes. It is conceivable therefore that death of cerebellar cells may also be a clinical feature of HPS patients, a pathological event which has not been reported in the literature. In general, the bf mutant may be a potentially new and useful model for understanding Purkinje cell development and function.
Chintala
Sreenivasulu
S
Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, NY, USA. sreenivasulu.chintala@roswellpark.org
Novak
Edward K
EK
Spernyak
Joseph A
JA
Mazurchuk
Richard
R
Torres
German
G
Patel
Suchith
S
Busch
Kristie
K
Meeder
Beth A
BA
Horowitz
Judith M
JM
Vaughan
Mary M
MM
Swank
Richard T
RT
D000375:Aging; D000818:Animals; D001921:Brain / Q000473:pathology / Q000502:physiology; D064026:Calbindins; D016923:Cell Death / Q000235:genetics; D002531:Cerebellum / Q000473:pathology / Q000502:physiology*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D018737:Hand Strength / Q000502:physiology; D022861:Hermanski-Pudlak Syndrome / Q000235:genetics / Q000473:pathology; D007150:Immunohistochemistry; D008279:Magnetic Resonance Imaging; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009043:Motor Activity / Q000235:genetics*; D009929:Organ Size; D011187:Posture / Q000502:physiology; D011689:Purkinje Cells / Q000502:physiology*; D013216:Reflex, Startle / Q000235:genetics; D064030:S100 Calcium Binding Protein G / Q000378:metabolism; D033921:Vesicular Transport Proteins / Q000235:genetics* / Q000378:metabolism*
D064026:Calbindins; D005904:Glial Fibrillary Acidic Protein; D064030:S100 Calcium Binding Protein G; D033921:Vesicular Transport Proteins; C472129:Vps33a protein, mouse