Adeno-Associated Virus Type 2 Vector-Mediated Glial Cell Line-Derived Neurotrophic Factor Gene Transfer Induces Neuroprotection and Neuroregeneration in a Ubiquitin-Proteasome System Impairment Animal Model of Parkinson’s Disease

Abstract

Background: The impairment of the ubiquitin-proteasome system (UPS) is a cellular mechanism underlying the neurodegenerative process in Parkinson’s disease (PD). A mouse model induced by the selective proteasome inhibitor lactacystin targeting on substantia nigra has been demonstrated to be valuable in investigating etiopathogenesis and neuroprotection for PD. Objective: In the present study, we used adeno-associated virus type 2 vector (AAV2) encoding glial cell line-derived neurotrophic factor (GDNF) injected into the striatum of this animal model to test the effectiveness and possible mechanisms of GDNF gene therapy. Results: Our results showed that AAV2-mediated GDNF gene therapy significantly attenuated lactacystin-induced loss of nigral dopamine (DA) neurons and striatal DA levels. Furthermore, we found that GDNF protein is mostly expressed in astrocytes in the subventricular zone (SVZ) and dentate gyrus (DG). AAV2-mediated GDNF therapy can induce neurogenesis in the SVZ and DG, and increase the number of nigral newborn DA neurons. Conclusion: These data indicate that AAV2-mediated GDNF gene therapy can protect the nigral DA neurons from the UPS impairment-induced degeneration, which may partly result from the nigral DA neuron regeneration in the brain, and such experimental results may have implications for the treatment of PD.

Combining NT3-overexpressing MSCs and PLGA microcarriers for brain tissue engineering: A potential tool for treatment of Parkinson's disease

“…Poly(D,L-lactide-co-glycolide) with lactic: glycolic units ratio of 50:50 (Mw=38,000 Da) was used to synthesize microcarriers via water-in-oil-in-water (W/O/W) emulsion-extractionevaporation process [31,36]. Briefly, internal aqueous phase including 60 mL of 16…”

“…Mesenchymal stem cells are proposed as the best source for cell-based therapies of neurological disorders because of their remarkable neuro-differentiational characteristic, immunomodulatory features [13], and capacity to migrate toward source of lesions in brain [14]. Moreover, some studies have reported that bone marrow mesenchymal stem cells (BMSCs) can be induced into DA-neurons due to their ability to secret tyrosine hydroxylase (TH) [15] and other neural markers [10,16,17]. Also, some studies showed that transplantation of MSCs into adult intact rats lead to significant elevation of TH secretion and DA levels in the striatum [10,18].…”

Stem Cell–Based Tissue Replacement After Stroke

“…NSCs can modulate the local environment to prevent such influences 59 , thereby supporting the actions of neighboring neurons as a “bystander effect.” NSCs can, among others, also produce a broad spectrum of trophic factors, such as nerve growth factor NGF, brain-derived neurotrophic factor (BDNF), and glia-derived neurotrophic factor (GDNF) 60 , which play pivotal roles in neuroprotection, as they mitigate caspase-mediated apoptosis in the injured CNS 61 . GDNF has been reported to be neuroprotective 62 by promoting cell survival, but also enhances axonal outgrowth and synaptogenesis. To augment the growth factor-mediated neuroprotective potential of NSCs, therapeutic approaches that employ the induced overexpression of factors such as BDNF 63 for the treatment of ischemic stroke, or GDNF 64 for hemorrhagic stroke, have been suggested.…”

Increased Physiological GDNF Levels Have No Effect on Dopamine Neuron Protection and Restoration in a Proteasome Inhibition Mouse Model of Parkinson’s Disease

“…Available data suggest that in the dopaminergic neurons of the midbrain RET receptor is essential to mediate GDNF neuroprotective and neurorestorative effects in MPTP-induced animal models (Kowsky et al, 2007;Drinkut et al, 2016;Conway et al, 2020;Conway and Kramer, 2022). Similarly, GDNF protected midbrain dopamine neurons from proteasome inhibitor lactacystin induced degeneration in vitro (Li et al, 2007) and in vivo (Du et al, 2008(Du et al, , 2013. Moreover, recent results from placebo-controlled clinical studies suggest that at least some patients benefit from ectopic GDNF delivery (Barker et al, 2020), providing rationale for further work in that direction.…”