SUMO1-derived peptide inhibitor a potential treatment for Parkinson’s disease

Researchers from the Chinese University of Hong Kong (CUHK) have developed a novel peptide inhibitor that can reduce the accumulation of α-synuclein amyloid fibrils, slowing down the progress of deterioration in patients with Parkinson’s disease and other types of neurodegenerative diseases.

Parkinson’s disease is one of the most common neurodegenerative diseases in the elderly. It can be divided into idiopathic type and those with secondary causes. Most cases are idiopathic, triggered by impaired functions of the nervous system in the brain. Although there is no clear medical evidence for its cause at this stage, various studies have found that α-synuclein aggregates in the brain nerve cells of patients with Parkinson’s disease and dementia, and this protein aggregate is the main component of Lewy bodies. “The accumulation of α-synuclein amyloid fibrils in the brain is linked to Parkinson’s disease and other synucleinopathies,” wrote the researchers. [Arch Neurol 2001;58:186-190]

α-synuclein is toxic to neurons and leads to progressive loss of cognitive and motor functions. The intermediate species in the early aggregation phase of α-synuclein are involved in the emergence of amyloid toxicity and considered to be the most neurotoxic. [Biochem J 2012;443:719-726]

“Most patients with Parkinson’s disease and dementia have Lewy bodies composed of aggregates of α-synuclein in their brain. We believe the progression of the disease can be delayed with a therapy that could inhibit α-synuclein accumulation,” stated Professor Michael Chan of the School of Life Sciences at CUHK.

Following the unexpected observation by the lead author, Ms Zhaohui Liang of CUHK’s School of Life Sciences, that certain variants of SUMO1, a ubiquitously expressed human protein, were effective against α-synuclein aggregation, the team identified a minimal functional core, SUMO1(15-55), that could bind to the α-synuclein protein and directly suppress its aggregation, and subsequently proposed the molecular mechanism of this inhibition. [Cell Chem Biol 2021;S2451-9456(20)30519-5]

Molecular modelling, site-directed mutagenesis, and binding studies were used to elucidate the mode of interaction, namely, via the binding of either of the two SIM sequences on α-synuclein to a putative hydrophobic binding groove on SUMO1(15–55).

The researchers subsequently collaborated with Professor Edwin Chan of Gerald Choa Neuroscience Centre, CUHK, to further evaluate the neuroprotective effect of SUMO1(15-55) in a Drosophila model of PD. [J Biol Chem 2005;280:2873-2878] Notably, treatment of Drosophila larvae with the SUMO1(15-55) peptide resulted in ameliorated neurodegenerative disease symptoms, highlighting the potential of the peptide as a therapeutic inhibitor against Parkinson’s disease. “Our studies showed that SUMO1(15–55) reduces α-synuclein-induced cytotoxicity in cell-based and Drosophila disease models,” noted the researchers.

The researchers are currently working on improving the biostability, brain-targeting ability and therapeutic efficacy of the peptide inhibitor, with the aim of eventually using an optimized construct to treat patients in the clinic.