Severe Neurodegeneration with Impaired Autophagy Mechanism Triggered by Ostm1 Deficiency

Abstract

Background: Although loss of the Ostm1 gene leads to the most severe form of osteopetrosis, Ostm1 is expressed in other tissues, including the CNS. Results: Independently of hematopoietic lineages, loss of Ostm1 results in acute neurodegeneration with enhanced autophagy. Conclusion: We present evidence for an Ostm1 cell-autonomous role in neurons. Significance: This study shows a novel molecular pathogenic mechanism for neurodegeneration-related diseases.

Role of Ostm1 Cytosolic Complex with Kinesin 5B in Intracellular Dispersion and Trafficking

“…Interestingly, KIF5B interacts with importin ␤/karyopherin like Ostm1 and is a member of a multiprotein complex in human neuroretina (41). These shared interactions suggest that this protein triad could play a role in gl/gl retinal neurodegeneration (11).…”

“…In Ostm1-null osteoclasts, the lack of Ostm1 vesicles linked to KIF5B cargos would elucidate the virtual absence of ruffled border, resulting in nonfunctional secretory cells, inefficient bone resorption, and osteopetrosis (9). Similarly, defective secretory lysosome and/or organelle dispersion due to loss of Ostm1 is likely the cellular mechanism causing the altered gl/gl immune cell response and hair pigmentation by melanosome clumping (8,10,11). Moreover, the role of Ostm1 in trafficking can also underlie the severe neuronal degeneration with impaired autophagosome targeting to lysosomes in gl/gl mice (11).…”

“…The Ostm1 gene was shown to play additional roles in the brain and in hair pigmentation. Recently, characterization of Ostm1 in the brains of gl/gl mice following correction of osteoclast defects revealed impaired autophagy exclusively in neurons, which led to neuronal degeneration and early death (11). These mice also exhibited neuroretinal degeneration.…”

Hematopoietic cell transplantation for a child with OSTM1 osteopetrosis

“…Although not completely elucidated, the protein has been shown to play a primary, autonomous role in neuronal homeostasis independent of the hematopoietic lineage, in addition to its critical role in osteoclast function. 10,12 Heraud et al have shown that, despite functional rescue of the hematopoietic defects in OSTM1-deficient mice after HCT, neurodegeneration continues, leading to local inflammation and eventual cell death. Although the hematopoietic and neurologic effects are seemingly discrete, it is unknown whether there can be cross-correction of the nervous system from transplanted hematopoietic cells if HCT is performed before neuronal damage, a concept previously reported in patients with metabolic conditions including purine nucleoside phosphorylase (PNP) deficiency, 13,14 a mannosidosis, Hurler syndrome, and cerebral X-linked adrenoleukodystrophy.…”

Bone-brain crosstalk and potential associated diseases

“…Moreover, hormonal imbalances are also well known to elicit profound effects on the central regulation of food intake, energy expenditure and multiple physiological functions [10][11][12][13]. Importantly, hormone levels are known to fluctuate with aging and elegant studies have recently demonstrated that blood derived from young mice can reverse the decline of hippocampal neurogenesis and memoryrelated behaviors [14][15][16]. Taken together these observations highlight the fundamental importance of endocrine cues and reciprocal interactions between organs for the maintenance of whole-body homeostasis and the function of the CNS.…”