Abstract
Ankyrin-rich BTB/POZ domain containing protein-2 or BPOZ-2, a scaffold protein, has been recently shown to control the degradation of many biological proteins ranging from embryonic development to tumor progression. However, its role in the process of neuronal diseases has not been properly explored. Since, abnormal clearance of metabolic proteins contributes to the development of alpha-synuclein (α-syn) pathologies in Parkinson’s disease (PD), we are interested to explore if BPOZ-2 participates in the amelioration of α-syn in vivo in basal ganglia. Here we report that lentiviral administration of bpoz-2 gene indeed lowers the burden of α-syn in DA neurons in the nigra of A53T transgenic (A53T-Tg) mouse. Our detailed immunological analyses have shown that the overexpression of bpoz-2 dramatically improves both somatic and neuritic α-syn pathologies in the nigral DA neurons. Similarly, the specific ablation of bpoz-2 by lentiviral-shRNA stimulates the load of monomeric and polymeric forms of α-syn in the nigral DA neurons of A53T-Tg. While investigating the mechanism, we observed that BPOZ-2 was involved in a protein-protein association with PINK1 and therefore could stimulate PINK1-dependent autophagic clearance of α-syn. Our results have demonstrated that bpoz-2 gene delivery could have prospect in the amelioration of alpha-synucleinopathy in PD and other Lewy body diseases.
Highlights
Since, accumulation of α -syn is regulated by numerous signaling events involving many oxidative[1], inflammatory[2 ], metabolic[3 ], epigenetic[4] and neurotoxic factors[5,6,7,8,9]; identification of a specific molecular target is a major challenge in order to understand the molecular mechanism of alpha-synucleinopathy and develop an efficient therapy for the treatment of Parkinson’s disease (PD)
The nigral expression of BPOZ-2 was continued to decrease with age and found to be strongly reduced (*p < 0.01; = 0.007) in 9-months’ old male A53T transgenic (A53T-Tg) mice (n = 3) compared to wild type mice (Fig. 1C,D) suggesting that A53T-Tg is associated with strong age-dependent reduction of BPOZ-2 in their nigra
Our dual immunostaining analyses of tyrosine hydroxylase (TH; red) and BPOZ-2 (Fig. 1K) followed by co-localization analyses in Fiji colocz tool (Fig. 1L; right) further indicated that nigral DA neurons of A53T-Tg animals expressed very low amount of BPOZ-2 with a low, but positive Pearson coefficient (0.320 ± 0.122 from 10 different images) (Fig. 1K; right), whereas neuronal expression of BPOZ-2 remained high in the nigra of Non-Tg mice (Fig. 1K; left), which was reflected by a high Pearson coefficient (0.75 ± 0.141 from 10 different images) (Fig. 1L; left)
Summary
Accumulation of α -syn is regulated by numerous signaling events involving many oxidative[1], inflammatory[2 ], metabolic[3 ], epigenetic[4] and neurotoxic factors[5,6,7,8,9]; identification of a specific molecular target is a major challenge in order to understand the molecular mechanism of alpha-synucleinopathy and develop an efficient therapy for the treatment of PD. BPOZ-2, an ankyrin repeat and BTB/POZ domain containing protein-2, serves as an important upstream regulator of wide-range of cellular pathways ranging from cell growth[10] and development to apoptotic cell death[11] and the clearance of metabolically defective proteins[12]. Its role has never been explored in the amelioration of alpha-synucleinopathy in vivo in the nigra. It primarily serves as a growth suppressor protein, and because of its large size, it mainly participates in protein–protein interaction with wide range of intracellular proteins including ubiquitin ligase Cul-3 and ubiquitin. We report that lentiviral administration of bpoz-2 gene lowers the burden of α -syn in DA neurons in the nigra of A53T-Tg mouse. Our results have demonstrated that bpoz-2 gene delivery could be prospective in the amelioration of alpha-synucleinopathy in PD and other Lewy body diseases
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