Mechanistic Insight from Preclinical Models of Parkinson’s Disease Could Help Redirect Clinical Trial Efforts in GDNF Therapy

Abstract

Parkinson’s disease (PD) is characterized by four pathognomonic hallmarks: (1) motor and non-motor deficits; (2) neuroinflammation and oxidative stress; (3) pathological aggregates of the α-synuclein (α-syn) protein; (4) neurodegeneration of the nigrostriatal system. Recent evidence sustains that the aggregation of pathological α-syn occurs in the early stages of the disease, becoming the first trigger of neuroinflammation and subsequent neurodegeneration. Thus, a therapeutic line aims at striking back α-synucleinopathy and neuroinflammation to impede neurodegeneration. Another therapeutic line is restoring the compromised dopaminergic system using neurotrophic factors, particularly the glial cell-derived neurotrophic factor (GDNF). Preclinical studies with GDNF have provided encouraging results but often lack evaluation of anti-α-syn and anti-inflammatory effects. In contrast, clinical trials have yielded imprecise results and have reported the emergence of severe side effects. Here, we analyze the discrepancy between preclinical and clinical outcomes, review the mechanisms of the aggregation of pathological α-syn, including neuroinflammation, and evaluate the neurorestorative properties of GDNF, emphasizing its anti-α-syn and anti-inflammatory effects in preclinical and clinical trials.

Neurodegenerative Diseases: Unraveling the Heterogeneity of Astrocytes

“…Oxidative stress, impaired lysosomal degradation mechanisms, and mitochondrial dysfunction have been associated with pathological α-syn accumulation [ 144 , 145 ]. Research suggests that this abnormal accumulation would result in a change from A2 astrocytes to A1 reactive astrocytes, indicating that increasing the A1/A2 ratio of reactive astrocytes drives the abnormal aggregation and spread of α-syn and, therefore, PD progression.…”

PPARs and Their Neuroprotective Effects in Parkinson’s Disease: A Novel Therapeutic Approach in α-Synucleinopathy?

“…The α-syn is a small protein 140 amino acids long, which can adopt different conformations depending on the environment and easily interacts with other ligands such as lipids. This protein is physiologically expressed at high concentrations in the brain and is involved in many critical neurological processes such as [ 2 , 10 , 11 ]: synaptic maintenance, mitochondrial and plasmatic membrane homeostasis, proteasome function, dopamine metabolism, and chaperone protein activity ( Figure 1 A).…”