scyllo-Inositol Promotes Robust Mutant Huntingtin Protein Degradation

Lai, Aaron Y.; Lan, Cynthia P.; Hasan, Salwa; Brown, Mary Elizabeth; McLaurin, JoAnne

doi:10.1074/jbc.m113.501635

Cited by 17 publications

(12 citation statements)

References 56 publications

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“…The scyllo-inositol reduction we found in AAS users is intriguing given its large effect size, the trend negative association between lifetime AAS dose and scyllo-inositol levels, and reports that scyllo-inositol can reduce the effects of neurotoxic proteins including β-amyloid, α-synuclein, and huntingtin (Lai et al, 2014; McLaurin et al, 2000; Vekrellis et al, 2009). Given observations that the commonly used AAS 17β-trenbolone and methandienone increase β-amyloid levels in male rats (Ma and Liu, 2015) and enhance β-amyloid toxicity in neuronal cultures (Caraci et al, 2011), it follows that human AAS users may be at increased risk for β-amyloid toxicity, and that this risk could be compounded by scyllo-inositol depletion.…”

Section: Discussionmentioning

confidence: 74%

Brain and cognition abnormalities in long-term anabolic-androgenic steroid users

Kaufman

Janes

Hudson

et al. 2015

Drug and Alcohol Dependence

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Background Anabolic-androgenic steroid (AAS) use is associated with psychiatric symptoms including increased aggression as well as with cognitive dysfunction. The brain effects of long-term AAS use have not been assessed in humans. Methods This multimodal magnetic resonance imaging study of the brain compared 10 male weightlifters reporting long-term AAS use with 10 age-matched weightlifters reporting no AAS exposure. Participants were administered visuospatial memory tests and underwent neuroimaging. Brain volumetric analyses were performed; resting-state fMRI functional connectivity (rsFC) was evaluated using a region-of-interest analysis focused on the amygdala; and dorsal anterior cingulate cortex (dACC) metabolites were quantified by proton magnetic resonance spectroscopy (MRS). Results AAS users had larger right amygdala volumes than nonusers (P=0.002) and reduced rsFC between right amygdala and frontal, striatal, limbic, hippocampal, and visual cortical areas. Left amygdala volumes were slightly larger in AAS users (P=0.061) but few group differences were detected in left amygdala rsFC. AAS users also had lower dACC scyllo-inositol levels (P=0.004) and higher glutamine/glutamate ratios (P=0.028), possibly reflecting increased glutamate turnover. On a visuospatial cognitive task, AAS users performed more poorly than nonusers, with the difference approaching significance (P=0.053). Conclusions Long-term AAS use is associated with right amygdala enlargement and reduced right amygdala rsFC with brain areas involved in cognitive control and spatial memory, which could contribute to the psychiatric effects and cognitive dysfunction associated with AAS use. The MRS abnormalities we detected could reflect enhanced glutamate turnover and increased vulnerability to neurotoxic or neurodegenerative processes, which could contribute to AAS-associated cognitive dysfunction.

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Section: Discussionmentioning

confidence: 74%

Brain and cognition abnormalities in long-term anabolic-androgenic steroid users

Kaufman

Janes

Hudson

et al. 2015

Drug and Alcohol Dependence

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“…[69] Likewise, scyllo-inositol reduces the number of neuronal aggregates and inclusions containing polyglutamineexpanded huntingtin protein in Huntington disease,a nd does this by reducing the amount of mutant protein produced. [70] Amyloid deposits can also form in the islets of Langerhans and may contribute to the development of diabetes: scyllo-, myo-, and epi-inositols are ineffective in preventing the formation of these amyloid deposits. [71] In rats,s eizures induced by pentylenetetrazole were reduced in severity following the administration of scylloinositol.…”

Section: Scyllo-inositol and Neurological Disordersmentioning

confidence: 99%

ChemInform Abstract: The “Other” Inositols and Their Phosphates: Synthesis, Biology, and Medicine (with Recent Advances in myo‐Inositol Chemistry)

2016

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“…Although further studies are necessary to clarify whether the low sI signal we found in AAS users reflects low sI concentration, a low sI/Aβ ratio, or a combination of these effects, any of these scenarios -via reduction of sI availability to complex with and help eliminate Aβcould lead to or reflect increased Aβ burdens and risk for developing AD/ADRD. Because sI also prevents clumping of other neurotoxic proteins, including α-synuclein and Huntingtin proteins associated with the development of Parkinson's and Huntington's diseases, respectively (Vekrellis et al, 2009;Lai et al, 2014), the low sI signal we found in long-term supraphysiologic-dose AAS users could indicate that they are at increased risk for developing other neurodegenerative disorders.…”

Section: Supraphysiologic-dose Aas Exposures Are Associated With Neurmentioning

confidence: 83%

Supraphysiologic-dose anabolic–androgenic steroid use: A risk factor for dementia?

Kaufman

Kanayama

Hudson

et al. 2019

Neuroscience & Biobehavioral Reviews

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Supraphysiologic-dose anabolic-androgenic steroid (AAS) use is associated with physiologic, cognitive, and brain abnormalities similar to those found in people at risk for developing Alzheimer's Disease and its related dementias (AD/ADRD), which are associated with high brain β-amyloid (Aβ) and hyperphosphorylated tau (tau-P) protein levels. Supraphysiologic-dose AAS induces androgen abnormalities and excess oxidative stress, which have been linked to increased and decreased expression or activity of proteins that synthesize and eliminate, respectively, Aβ and tau-P. Aβ and tau-P accumulation may begin soon after initiating supraphysiologic-dose AAS use, which typically occurs in the early 20s, and their accumulation may be accelerated by other psychoactive substance use, which is common among non-medical AAS users. Accordingly, the widespread use of supraphysiologic-dose AAS may increase the numbers of people who develop dementia. Early diagnosis and correction of sex-steroid level abnormalities and excess oxidative stress could attenuate risk for developing AD/ADRD in supraphysiologic-dose AAS users, in people with other substance use disorders, and in people with low sex-steroid levels or excess oxidative stress associated with aging.

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scyllo-Inositol Promotes Robust Mutant Huntingtin Protein Degradation

Cited by 17 publications

References 56 publications

Brain and cognition abnormalities in long-term anabolic-androgenic steroid users

Brain and cognition abnormalities in long-term anabolic-androgenic steroid users

ChemInform Abstract: The “Other” Inositols and Their Phosphates: Synthesis, Biology, and Medicine (with Recent Advances in myo‐Inositol Chemistry)

Supraphysiologic-dose anabolic–androgenic steroid use: A risk factor for dementia?

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