Increased telomerase improves motor function and alpha-synuclein pathology in a transgenic mouse model of Parkinson’s disease associated with enhanced autophagy

Abstract

Highlights Telomerase activators (TA) increase Tert expression in brains of a PD mouse model. Activator treatment improves PD motor symptoms: gait and balance. Activators reduce different forms of alpha-synuclein in brains of transgenic mice. Decreased autophagy markers LC3 and p62 suggest a better protein degradation. Our preclinical data suggest a use of TA to ameliorate PD-like symptoms.

Cannabidiol Induces Autophagy to Protects Neural Cells From Mitochondrial Dysfunction by Upregulating SIRT1 to Inhibits NF-κB and NOTCH Pathways

“…In the development of PD, the regulation of autophagy is essential (Zhu et al, 2019;Wan et al, 2020). The damage to the autophagy pathway and the resulting accumulation of misfolded α-synuclein and other proteins aggregates represent the common pathobiological characteristics of neurodegenerative diseases such as PD (Erb and Moore, 2020;Kwon et al, 2020).…”

Telomerase in Brain: The New Kid on the Block and Its Role in Neurodegenerative Diseases

“…A recent study by Wan and colleagues applied both activators, TA-65 and GRN510, in a pilot study on two-year-old female mice for 3 months which resulted in a significant increase of mTert expression in brain tissue [ 67 ]. Analysing motor coordination as a read-out for age-related brain function, the study found a significant improvement of strength and coordination in a static rod test where both treatments increased the time on the rod similarly to that of adult (10 months old) mice while only that for GRN510 was statistically significant [ 67 ]. These results are similar to those described by Eyolfson and co-authors who treated rats for one month with TA-65 before inflicting a brain injury.…”

“…Both activators significantly increased mTert gene expression in both sexes after 14 months of treatment starting at 4 months. Additionally, in vitro experiments on cultured primary embryonic mouse neurons at a time point where these neurons were no longer positive for telomerase activity [ 41 ] confirmed specifically that neurons were able to upregulate mTert expression after activator treatment [ 67 ].…”

“…Since impaired motor coordination is an important symptom for PD, behavioural tests for motor activity such as the rotarod test, gait test and walking speed were employed to characterise treatment effects [ 67 ]. Interestingly, results from the rotarod test showed some striking sex specificities: in females only TA-65 improved motor parameters, in males a significant improvement was achieved exclusively with GRN510.…”

“…Gait analysis measures stride length and width as well as variations therein and is similar to clinical tests used on PD patients [ 72 ]. Both activators greatly improved the walking speed as well as the length and width of strides, with a reduction in stride variation [ 67 ].…”