alpha-synuclein and Diabetes-Mellitus--Type-1

Growing evidence suggests an association between Parkinson's disease (PD) and diabetes mellitus (DM). At the cellular level, long-term elevated levels of glucose have been shown to lead to nigrostriatal degeneration in PD models. However, the underlying mechanism is still unclear. Previously, we have elucidated the potential of type 2 diabetes mellitus (T2DM) in facilitating PD progression, involving aggregation of both alpha-synuclein (α-syn) and islet amyloid polypeptide in the pancreatic and brain tissues. However, due to the complicated effect of insulin resistance on PD onset, the actual mechanism of hyperglycemia-induced dopaminergic degeneration remains unknown.. We employed the type 1 diabetes mellitus (T1DM) model induced by streptozotocin (STZ) injection in a transgenic mouse line (BAC-α-syn-GFP) overexpressing human α-syn, to investigate the direct effect of elevated blood glucose on nigrostriatal degeneration.. STZ treatment induced more severe pathological alterations in the pancreatic islets and T1DM symptoms in α-syn-overexpressing mice than in wild-type mice, at one month and three months after STZ injections. Behavioral tests evaluating motor performance confirmed the nigrostriatal degeneration. Furthermore, there was a marked decrease in dopaminergic profiles and an increase of α-syn accumulation and Serine 129 (S129) phosphorylation in STZ-treated α-syn mice compared with the vehicle-treated mice. In addition, more severe neuroinflammation was observed in the brains of the STZ-treated α-syn mice.. Our results solidify the potential link between DM and PD, providing insights into how hyperglycemia induces nigrostriatal degeneration and contributes to pathogenic mechanisms in PD.

Topics: alpha-Synuclein; Animals; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Disease Models, Animal; Dopamine; Hyperglycemia; Mice; Mice, Transgenic; Parkinson Disease

Children with obesity and those with type 1diabetes (T1D) exhibit subtle neurocognitive deficits, the mechanism of which remains unknown. α-synuclein plays a fundamental role in neurodegeneration. Moreover, its role in glucose and lipids metabolism is emerging. This study aims to assess whether α-synuclein is correlated with the degree of neurodegeneration in children with obesity and those with T1D in comparison to healthy controls and correlate it to various neurocognitive and metabolic parameters.. Forty children with obesity, 40 children with T1D and 40 matched-healthy controls were assessed for anthropometric measurements and blood-pressure. Cognitive evaluation was performed using Stanford-Binet scale and Barkley Deficits in Executive Functioning (EF) Scale-Children and Adolescents. α-synuclein, fasting lipids and glucose were measured with calculation of the homeostatic model of insulin-resistance and estimated-glucose disposal rate.. Children with obesity and those with T1D had significantly higher α-synuclein (p < 0.001) and total EF percentile (p = 0.001) than controls. α-synuclein was negatively correlated to total IQ (p < 0.001 and p = 0.001), and positively correlated with total EF percentile (p = 0.009 and p = 0.001) and EF symptom count percentile (p = 0.005 and p < 0.001) in children with T1D and obesity, respectively. Multivariate-regression revealed that α-synuclein was independently related to age (p = 0.028), diabetes-duration (p = 0.006), HbA1C% (p = 0.034), total IQ (p = 0.013) and EF symptom count percentile (p = 0.003) among children with T1D, and to diastolic blood-pressure percentile (p = 0.013), waist/hip ratio SDS (p = 0.007), total EF percentile (P = 0.033) and EF symptom count percentile (p < 0.001) in children with obesity.. α-synuclein could have a mechanistic role in neurocognitive deficit among children with obesity and T1D.

Topics: Adolescent; alpha-Synuclein; Blood Glucose; Diabetes Mellitus, Type 1; Executive Function; Glucose; Glycated Hemoglobin; Humans; Insulins; Lipids; Obesity

Diabetic retinopathy (DR) is the leading cause of irreversible vision loss in adults. Parkinson's disease (PD) is a chronic progressive neurodegenerative movement disorder characterized by progressive loss of dopaminergic neurons in substantia nigra of midbrain. Evidences suggest that diabetic patients tend to show higher incidence of PD, advocating a shared mechanism between both the diseases. Interestingly, disruption of the dopaminergic system, which is an important causative factor in PD, has also been observed in DR. It is reported that retinal dopamine and tyrosine hydroxylase protein levels are downregulated, and dopaminergic amacrine cells appear to be degenerating in the animal models of DR. Further, injecting the diabetic mice with dopamine-restoring or dopamine-activating drugs already used to treat PD can restore dopamine levels and significantly improve diabetes-associated visual dysfunction in the early stage. Conversely, drugs already in use for insulin resistance also show protective effects in PD. Furthermore, α-Synuclein pathology of PD can be induced solely by high glucose in diabetic animal models. In conclusion, these findings establish an important role of dopamine deficiency as a common contributing factor in DR and PD. The changes in the ocular of diabetes involve dopamine metabolism disturbance, mimicking PD at the molecular level. Consequently, we could consider DR as at least partially the PD like molecular pathology in the eye. Importantly, indicating that dopamine decrease may play a role in DR will lead to a better understanding of the high rate of comorbidity reported between diabetes and PD, and reveal new therapeutic avenues for DR and other disorders that involve dopamine deficiency.

Topics: alpha-Synuclein; Animals; Blood Glucose; Diabetes Mellitus, Type 1; Diabetic Retinopathy; Disease Progression; Dopamine; Dopaminergic Neurons; Humans; Mesencephalon; Mice; Models, Theoretical; Parkinson Disease; Retina; Substantia Nigra; Tyrosine 3-Monooxygenase