Parkinson’s disease (PD) is the second most common neurodegenerative disease after Alzheimer’s disease (AD) in human, presenting mainly motor discoordination accompanied by various non-motor symptoms, such as cognitive impairments[1]. Progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the formation of cytoplasmic inclusions, called Lewy Bodies (LBs), are the two major neuropathological hallmarks of PD[2]. LBs are primarily composed of misfolded α-syn, which plays a crucial role in PD pathogenesis[3]. The etiology of PD is not yet clear. Most PD cases are sporadic, associated with different contributing risk factors such as aging and neurotoxins, etc.[4]. Available evidence suggests that certain metabolic diseases may also serve as risk factors for PD, such as diabetes mellitus (DM)[5]. DM is a group of complex metabolic diseases characterized by impaired glucose metabolism and subsequent hyperglycemia resulting from defects in insulin secretion and efficiency[6]. Based on the concepts of being “insulin-sensitive” and “insulin-insensitive”[7], DM can be divided into type 1 diabetes mellitus (T1DM) with insufficient insulin secretion due to progressive destruction of pancreatic β cells, and type 2 diabetes mellitus (T2DM) with the lack of appropriate insulin response[8–11].
PD and DM share similarities in multiple aspects, including epidemiology, etiology and pathogenesis. First, epidemiologically, DM presents as a risk factor for PD. Both PD and DM are of multifactorial origins with high prevalence. Diabetes is among the most prevalent chronic diseases, and researchers predicted a near doubling of patients with DM by 2030 compared to figures obtained in 2000[12]. PD is a disease with an increasing prevalence in the elderlies, and the projected prevalence cases for PD are predicted to increase during the next 40 years[13]. Accumulating evidence suggests that DM constitutes a risk factor associated with increased neurodegenerative diseases[5]. The elevated risk of developing cognitive abnormalities in individuals with impaired glucose metabolism is well documented[14, 15]. Epidemiological studies indicate that patients with preexisting DM have an increased incidence of developing PD and often display parkinsonian symptoms[16–20]. Secondly, PD and DM have shared potential contributing factors and overlapping pathology. Environmental exposure, genetic susceptibility and lifestyle factors[21–23] are well-known PD and DM causal factors. Clinically, some diabetic patients exhibit pathologies related to striatal dopaminergic dysfunction[11, 24]. Furthermore, DM and PD also share common etiopathogenic features[15, 20], such as dopaminergic neuronal loss in SNpc and α-syn aggregation in the pancreatic β cells in diabetic patients[25].
Although a growing body of epidemiological and clinical data favor the association between DM and PD[26], to date, the molecular mechanisms by which elevated levels of blood glucose associates with the development of PD are still unclear. Experimental studies support the toxic role of hyperglycemia in the central nervous system (CNS)[27, 28]. Our previous study has suggested the possible role of protein co-aggregation during the interplay of the two diseases in a non-human primate model[29]. However, considering the influence of insulin resistance in amyloid protein aggregation[30], the mechanisms of hyperglycemia induced-neurodegeneration remain obscure. Of all the shared mechanisms of DM and PD, neuroinflammation has unneglectable importance. First, diabetes mediates many of its effects through inflammation. T2DM can present oxidative stress and peripheral inflammation[31]. Diabetic patients often show mild chronic inflammation, reflected by the elevation of peripheral blood cytokines such as interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α) and interleukin-1β (IL-1β)[32, 33]. Secondly, systemic inflammatory status is associated with the interruption of blood-brain barrier (BBB) integrity. Corrupted BBB may subsequently cause leukocyte infiltration, diffusion of cytokines and entry of toxins into the CNS[34, 35], therefore trigger neuroinflammation and activate microglia[36]. At last, prolonged microglial activation is proven to be a major factor in driving dopaminergic degeneration in PD[37]. From DM to systematic inflammation, which thereafter induces neuroinflammation and then promotes the onset and progress of PD, a lot of evidence is shown to explain the mechanism of hyperglycemia-induced neurodegeneration. As a matter of fact, many studies highlight the importance of DM-induced neuroinflammation and its link to neurodegenerative diseases, such as AD[38].
Therefore, to study the effect of hyperglycemia on the nigrostriatal pathway and better understand the mechanistic connection between DM and PD, we have employed. the streptozotocin (STZ) induced-T1DM model in the background of both wild type (WT) and α-syn transgenic mice. After characterizing the T1DM phenotypes, we investigated PD related features in the mice regarding motor dysfunction, dopaminergic neuron and terminal loss, and α-syn aggregation. We found that intraperitoneal injection (i.p.) of STZ exacerbated degeneration of dopaminergic neurons in the α-syn-overexpression mice, which were accompanied by an increase in α-syn aggregation and phosphorylation. Moreover, we observed markedly increased neuroinflammation in the nigrostriatal systems of STZ-injected α-syn mice, suggesting the potential mechanistic role of neuroinflammation connecting hyperglycemia and the subsequent PD-related alternations.