Date of Award

Fall 8-21-2020

Level of Access

Open-Access Thesis

Degree Name

Doctor of Philosophy (PhD)

Department

Biomedical Sciences

Advisor

Clifford J Rosen

Second Committee Member

Aaron Brown

Third Committee Member

Robert Burgess

Additional Committee Members

Juan Pablo Rodriguez

Calvin Vary

Abstract

α-Synuclein is a polypeptide encoded by the Snca gene, highly expressed in neurons, but it is also found in bones and adipose tissue. Co-expression analysis showed that Snca regulates skeletal homeostasis, and its deletion reduced estrogen deficiency-induced bone loss and weight gain. It is a major component of Lewy bodies (LB) in Parkinson’s disease (PD), leading to progressive immobilization and a range of nonmotor symptoms, including osteopenia, body composition alterations and insulin resistance. This thesis aimed to determine α-Synuclein’s intrinsic role in bone and adipose homeostasis. We discussed the PD pathophysiology emphasizing aspects of bone health and metabolism. By using in vivo models we showed conditional deletion of Snca in osteoblasts is insufficient to reduce bone loss after estrogen deficiency, however, sufficient to reduce weight gain and decrease marrow adipocyte expansion. Prrx1Cre off-target effects led to decreased in α-Synuclein expression in the brain, decreased serum catecholamines, and behavioral phenotypes. Mutant mice experienced a mild improvement in bone microarchitecture. Although not protected from diet-induced obesity, mutants showed smaller adipocytes in the inguinal fat, decreased adipogenesis and higher oxidative capacity, however, decreased insulin sensitivity. Interestingly, AdipoCre;Sncafl/fl mice showed no significant increase in inguinal adipose accrual, decreased weight gain and increased insulin sensitivity.

In vitro models of loss of α-Synuclein led to fragmented mitochondria, decreased adipogenesis, and pAKT and, increased levels of AKT, pIRβ and pSHC. Mutated α-Synuclein overexpression (A53Ttg/tg) led to higher adipogenesis, mitochondria size and increased levels of pAKT/AKT. There was no change in colocalization of α-Synuclein to mitochondria in cells with differential α-Synuclein expression. After insulin treatment, α-Synuclein relocated to the nuclei in controls, however, this response was not seen in A53Ttg/tg.

This work showed α-Synuclein regulates adipose tissue cell autonomously and it does affect, mildly, bone microarchitecture through its actions on osteoblasts. Moreover, we showed α-Synuclein regulates insulin response by affecting the levels of pAKT/AKT and phosphorylated insulin receptor β.

Future research is essential to understand the local and systemic effects of α-Synuclein signaling on bone remodeling and adipose metabolism to shed light into possible treatment targets for osteoporosis and insulin resistance in PD patients.

Share