Long-term adenosine A1 receptor activation-induced sortilin expression promotes α-synuclein upregulation in dopaminergic neurons

Mechanism underlying the regulation of sortilin expression and its trafficking function

“…As an example, it was reported that sortilin expression is prominently increased in vascular inflammatory and rheumatic diseases and that knockout of sortilin significantly reduces the inflammatory response (Goettsch et al, 2016). Our group also found that sortilin expression was upregulated in dopaminergic neurons during the progression of Parkinson's disease (PD)‐like impairment and that knockdown of sortilin ameliorated the accumulation of α‐synuclein in the substantia nigra (Lv et al, 2019). All these findings suggest that the abnormal expression or function of sortilin plays an important role in the pathogenesis of related diseases.…”

“…Furthermore, in various immune cells (dendritic cells, plasmacytoid DCs, basophils, eosinophils, macrophages, and T cells), sortilin mediates the intracellular transport of some inflammatory factors (interferon‐α [IFN‐α], interleukin 10 [IL‐10], IL‐12, and IL‐17A as well as IFN‐γ and IL‐6) to promote their exocytosis, promoting the progression of inflammatory and autoimmune diseases (Goettsch et al, 2016; Herda et al, 2012; Yabe‐Wada et al, 2016). In addition, sortilin transports prosaposin to the lysosome to decrease the level of sphingolipids in the cell membrane and mediates α‐synuclein intracellular trafficking to enhance its accumulation in neurons, resulting in the pathological progression of neurodegenerative diseases (Hu et al, 2010; Lv et al, 2019).…”

The Concept of an Epilepsy Brain Bank

“…In 1968, Dr. Ali Rajput created the first brain bank in Canada dedicated only to patients with Parkinson's disease (PD) and other movement disorders. Development of the Bank led to numerous international and local contributions and critical breakthroughs in the modern treatment of PD, only possible because every case has the full documentation of 1 (1) detailed longitudinal clinical history, frozen tissue, and complete neuropathologic examination (2)(3)(4)(5)(6). The bank has more than 400 brains from patients with PD and other movement disorders and it shares samples with national and international qualified scientists for free (1).…”

“…The bank is based at the Douglas Mental Health University Institute and has become one of the largest brain banks in the world. Currently, it houses more than 3,000 brains as well as a large relational database containing demographic, clinical and developmental histories from the donors 2 . The bank has brains from people who suffered from different neurodegenerative diseases such as PD and other dementias, schizophrenia, major depression, bipolar disorder, substance use disorder and patients who committed suicide.…”

“…Previous and ongoing investigations have demonstrated the involvement of adenosine A1 and A2A (A2AR) receptors in the pathophysiology of neurodegeneration in animal stroke models, which display post-stroke depression, cognitive dysfunction and increased post-stroke seizures ( 2 , 69 ). An important physical and functional interaction between A1Rs and glutamate AMPA receptors (AMPARs) in rat hippocampus contributes to the robust AMPAR endocytosis and persistent synaptic depression observed after prolonged A1R activation or during hypoxic insult ( 69 , 70 ).…”