Trehalose alleviates polyglutamine-mediated pathology in a mouse model of Huntington disease

Abstract

Inhibition of polyglutamine-induced protein aggregation could provide treatment options for polyglutamine diseases such as Huntington disease. Here we showed through in vitro screening studies that various disaccharides can inhibit polyglutamine-mediated protein aggregation. We also found that various disaccharides reduced polyglutamine aggregates and increased survival in a cellular model of Huntington disease. Oral administration of trehalose, the most effective of these disaccharides, decreased polyglutamine aggregates in cerebrum and liver, improved motor dysfunction and extended lifespan in a transgenic mouse model of Huntington disease. We suggest that these beneficial effects are the result of trehalose binding to expanded polyglutamines and stabilizing the partially unfolded polyglutamine-containing protein. Lack of toxicity and high solubility, coupled with efficacy upon oral administration, make trehalose promising as a therapeutic drug or lead compound for the treatment of polyglutamine diseases. The saccharide-polyglutamine interaction identified here thus provides a new therapeutic strategy for polyglutamine diseases.

Trehalose reduces retinal degeneration, neuroinflammation and storage burden caused by a lysosomal hydrolase deficiency

“…Trehalose treatment increased the median life span of the naglu –/ – mice by 6.4 weeks ( P  < 0.0001) (Figure 1(a)). Trehalose did not affect the body weight (Figure 1(b)) and did not cause any obvious adverse effects in WT mice, which is consistent with previous reports [34,37,41,42].

10.1080/15548627.2018.1474313-F0001Figure 1.Trehalose treatment increases the life span and reduces hyperactivity and anxiety-related behavior in naglu −/- mice.

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“…Trehalose has peculiar physical-chemical properties that confer chaperone-like activities [42], such as the ability to stabilize mutant proteins [41,42,58]. Moreover, protein aggregates in neurodegenerative diseases are substrates of autophagy [21,36,59,60], a pathway that is enhanced by trehalose [30–40].…”

“…Because impairment of autophagy has been described in several models of neuropathic lysosomal storage disorders caused by lysosomal enzyme deficiencies [28,29], we hypothesized that enhancement of autophagy might counteract disease progression in these disorders. We tested our hypothesis by using a mouse model of MPS IIIB (B6.129S6- Naglu tm1Efn /J) and trehalose, a known activator of autophagy [30–40] that reaches the mouse brain when provided orally [41], and evaluated the efficacy of this strategy through electrophysiological, behavioral, neuropathological and molecular analyses.…”

The R6 lines of transgenic mice: A model for screening new therapies for Huntington's disease

“…Tanaka et al (2004) have shown that various disaccharides can reduce polyglutamine aggregates and increase survival in an in vitro model of HD by binding to the expanded polyglutamine tails and stabilizing the partially unfolded polyglutamine-containing proteins. Importantly, oral administration of trehalose (the most effective of these disaccharides) starting at 21 days, was also proven to be beneficial in R6/2 mice by decreasing the number of polyglutamine aggregates in their brains, improving their motor dysfunction (as assessed by the rotarod and the footprint tests), and extending their lifespan by 10.14% (Tanaka et al, 2004). To date there has been no demonstration that trehalose crosses the blood brain barrier and therefore the exact mechanism of action of this disaccharide deserves further investigation.…”

Role of androgen receptor polyQ chain elongation in Kennedy's disease and use of natural osmolytes as potential therapeutic targets

“…It is important to note that certain osmolytes can be used to protect proteins from misfolding/aggregation and thereby maintaining/ restoring their intracellular functional activity (42,43), which otherwise may be prone to certain disease conditions. In fact, the utility of osmolytes as potential therapeutic interventions for neurodegenerative diseases, particularly associated with pathological conditions arising due to polyQ chain length extension, has been supported by studies in which osmolyte trehalose has been used as a preventive tool for Huntington's disease in transgenic animal mice (44). Osmolyte trehalose has been reported to activate macroautophagy possibly by the stabilization of the expanded polyQ protein and thereby preventing conversion of the expanded polyQ into aggregation-prone b-sheet-rich conformation (45,46).…”