Exp Gerontol. 2016 Aug;81:65-75. doi: 10.1016/j.exger.2016.04.023.

Early-onset motor impairment and increased accumulation of phosphorylated α-synuclein in the motor cortex of normal aging mice are ameliorated by coenzyme Q.

Takahashi K1, Ohsawa I1, Shirasawa T2, Takahashi M3.
  • 1Biological Process of Aging, Tokyo Metropolitan Institute of Gerontology, Itabashi-ku, Tokyo 173-0015, Japan.
  • 2Shirasawa Anti-Aging Medical Institute, Bunkyo-ku, Tokyo 113-0033, Japan.
  • 3Biological Process of Aging, Tokyo Metropolitan Institute of Gerontology, Itabashi-ku, Tokyo 173-0015, Japan. Electronic address: mmtaka@tmig.or.jp.



Brain mitochondrial function declines with age; however, the accompanying behavioral and histological alterations that are characteristic of Parkinson’s disease (PD) are poorly understood. We found that the mitochondrial oxygen consumption rate (OCR) and coenzyme Q (CoQ) content were reduced in aged (15-month-old) male mice compared to those in young (6-month-old) male mice. Concomitantly, motor functions, including the rate of movement and exploratory and voluntary motor activities, were significantly reduced in the aged mice compared to the young mice. In the motor cortex of the aged mouse brain, the accumulation of α-synuclein (α-syn) phosphorylated at serine129 (Ser129) significantly increased, and the level of vesicular glutamate transporter 1 (VGluT1) decreased compared with that in the young mouse brain. The administration of exogenous water-soluble CoQ10 to aged mice via drinking water restored the mitochondrial OCR, motor function, and phosphorylated α-syn and VGluT1 levels in the motor cortex. These results suggest that early-onset motor impairment and the increased accumulation of Ser129-phosphorylated α-syn in the motor cortex are ameliorated by the exogenous administration of CoQ10.

Copyright © 2016 Elsevier Inc. All rights reserved.


Coenzyme Q; Mitochondria; Motor cortex; Motor impairment; Normal aging; α-Synuclein

PMID: 27143639 



Parkinson’s disease (PD) is one of the most common neurodegenerative disorders and is characterized by the cardinal motor symptoms of resting tremor, rigidity, and bradykinesia (1-3) and by the progressive degeneration of neurons, which is most profound in the substantia nigra pars compacta (SNc) (4,5), and the presence of Lewy bodies (LBs) consisting of fibrillar aggregates of the synaptic protein a-synuclein (a-syn) (4). Many of these clinical and pathological features have been reported in familial PD and mouse models of PD, however, the majority of PD cases are sporadic, and little is known regarding the behavioral and histological alterations during normal aging.


We previously found that the earliest decline in mitochondrial function, as assessed by measuring the mitochondrial oxygen consumption rate (OCR), appeared in the brains of aged male mice at approximately 12 months of age (6). Because mitochondrial dysfunction has been reported in PD patients, we hypothesized that the aging-associated decline in brain mitochondrial function might be accompanied by early-onset motor impairment and accumulation of abnormal a-syn in specific regions of the brain.


OCR measurements at 3-month intervals revealed that a significant decline in the NADH-dependent OCR was observed in brain mitochondria of aged (15-month-old) C57BL/6 male mice compared with younger male mice. To examine whether the reduced brain mitochondrial OCR in aged mice was accompanied by their motor impairment, several behavioral tests, including the pole test (PT) that was designed for use with mice to measure bradykinesia as a very sensitive assessment of nigrostriatal dysfunction (7,8) (Figure 1), were performed.




Figure 1. Impaired motor function in aged mice using the pole test (PT). Mice were placed facing upward on the top of a vertical wooden pole (A) and were allowed to turn themselves downward and descend to the home cage (B) filled with bedding material in the pole test (PT). The time required for the animals to orient themselves downward and the total time required to descend the length of the pole back to the floor of the cage were measured.


In the PT, aged mice exhibited significantly slower movement than young (6-month-old) mice. Similarly, exploratory activity (rearing frequency) in the open field test (OFT) and voluntary locomotor activity in the home cage activity test (HCT) during the dark and total (dark plus light periods) were significantly reduced in aged mice compared to young mice.


Consistent with the characteristic motor symptoms of PD, accumulation of Ser129-phosphorylated a-syn in specific regions of the brains was examined. Contrary to abnormal a-syn accumulation in the dopaminergic neurons of the SNc or striatum in PD patients or mouse models of PD, many Ser129-phosphorylated a-syn-positive neurons were detected in the motor cortices of both young and aged mice (Figure 2), and the number of Ser129-phosphorylated a-syn-positive neurons was significantly greater in aged mice than in young mice.




Figure 2. Increased Ser129-phosphorylated a-syn accumulation in the motor cortex of aged mice (15m) compared to young mice (6m), and restoration of Ser129-phosphorylated a-syn levels in aged mice by exogenous CoQ10 administration via drinking water (15m-Q). Scale bar: 100 mm.


The aging-associated reduction in brain mitochondrial OCR can be rescued by increasing the CoQ content through the exogenous administration of water-solubilized coenzyme Q10 (CoQ10) (6). Therefore, in the current study, we measured the content of CoQ and mitochondrial OCR after CoQ10 administration via drinking water to young and aged mice. The administration of CoQ10 significantly increased the amounts of both CoQ10 and CoQ9 in brain mitochondria of aged mice, but not in young mice. In addition, the low mitochondrial OCR in the brains of aged mice was completely rescued by exogenous CoQ10 administration.


More importantly, the CoQ10-treated aged mice displayed significantly faster movement in the PT than did the control aged mice not administered CoQ10. Similarly, the voluntary locomotor activities during the dark, light, and total periods in the HCT were significantly enhanced in the CoQ10-administered aged mice.


We next examined whether the rescue of motor impairment by exogenous CoQ10 administration was accompanied by a restoration of Ser129-phosphorylated a-syn accumulation in the motor cortex, histochemical analysis was performed. Immunostaining of the motor cortex sections indicated that the number of Ser129-phosphorylated a-syn-positive neurons in the motor cortices of aged mice was significantly decreased by exogenous CoQ10 to levels comparable to those in young mice (Figure 2).


Importance of the study: our data indicate that early-onset brain mitochondrial dysfunction is accompanied by reduced exploratory and voluntary motor activities and increased accumulation of phosphorylated a-synuclein in the motor cortex, all of which are ameliorated by water-solubilized coenzyme Q via drinking water for a week.



  1. Tatton WG, Lee RG (1975) Evidence for abnormal long-loop reflexes in rigid Parkinsonian patients. Brain Res 100: 671-676.
  2. Logigian E, Hefter H, Reiners K, Freund HJ (1991) Does tremor pace repetitive voluntary motor behavior in Parkinson’s disease? Ann Neurol 30: 172-179.
  3. Phillips JG, Martin KE, Bradshaw JL, Iansek R (1994) Could bradykinesia in Parkinson’s disease simply be compensation? J Neurol 241: 439-447.
  4. Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M (1997) Alph-synuclein in Lewy bodies. Nature 388: 839-840.
  5. Spillantini MG, Crowther RA, Jakes R, Hasegawa M, Goedert M (1998) alpha- Synuclein in filamentous inclusions of Lewy bodies from Parkinson’s disease and dementia with Lewy bodies. Proc Natl Acad Sci U S A 95: 64696473.
  6. Takahashi K, Takahashi M (2013) Exogenous administration of coenzyme Q10 restores mitochondrial oxygen consumption in the aged mouse brain. Mech Ageing Dev 134: 580-586.
  7. Ogawa N, Hirose Y, Ohara S, Ono T, Watanabe Y (1985) A simple quantitative bradykinesia test in MPTP-treated mice. Res Commun Chem Pathol Pharmacol 50: 435-441.
  8. Matsuura K, Kabuto H, Makino H, Ogawa N (1997) Pole test is a useful method for evaluating the mouse movement disorder caused by striatal dopamine depletion. J Neurosci Methods 73: 45-48.



Mayumi Takahashi, Ph.D.

Biological Process of Aging,

Tokyo Metropolitan Institute of Gerontology, Tokyo 173-0015, Japan





Multiselect Ultimate Query Plugin by InoPlugs Web Design Vienna | Webdesign Wien and Juwelier SchönmannMultiselect Ultimate Query Plugin by InoPlugs Web Design Vienna | Webdesign Wien and Juwelier Schönmann