Effects and Mechanisms of Rapamycin Action on Experimental Neurodegeneration. / Pupyshev, A. B.; Korolenko, T. A.; Tikhonova, M. A.
In: Neurochemical Journal, Vol. 12, No. 4, 10.2018, p. 347-358.Research output: Contribution to journal › Review article › peer-review
}
TY - JOUR
T1 - Effects and Mechanisms of Rapamycin Action on Experimental Neurodegeneration
AU - Pupyshev, A. B.
AU - Korolenko, T. A.
AU - Tikhonova, M. A.
PY - 2018/10
Y1 - 2018/10
N2 - Rapamycin is a strong inducer of autophagy which binds with its target protein mTOR and causes inhibition of biosynthetic and mitotic cell activities. The review considers neuroprotective properties of autophagy induction by rapamycin. The most important feature of the neurodegenerative diseases is the accumulation of specific proteins, such as amyloid-, -synuclein, huntingtin, etc. Their accumulation is associated with the weakening of the cellular function of the protein quality control provided by the ubiquitin-proteasomal system and autophagy, including chaperone-mediated autophagy. In many cases, activation of autophagy by rapamycin is able to restore the quality control of proteins and organelles, to attenuate the accumulation of pathogenic proteins. Mechanisms of rapamycin therapeutic effects include activation of the clearance of neurons from pathogenic material and induction of both autophagosomal segregation of cellular material and the lysosomal flux by activating TFEB factor, which is the inductor of the lysosomal biogenesis. Short-term treatment with rapamycin has a positive therapeutic effect in models of acute brain injury (trauma, ischemia, hypoxia). Inhibition of neurodegeneration requires long-term therapy. Neuroprotective effect of rapamycin is higher if started at young age. Good results are achieved by prolonged treatment with rapamycin in intermittent mode.
AB - Rapamycin is a strong inducer of autophagy which binds with its target protein mTOR and causes inhibition of biosynthetic and mitotic cell activities. The review considers neuroprotective properties of autophagy induction by rapamycin. The most important feature of the neurodegenerative diseases is the accumulation of specific proteins, such as amyloid-, -synuclein, huntingtin, etc. Their accumulation is associated with the weakening of the cellular function of the protein quality control provided by the ubiquitin-proteasomal system and autophagy, including chaperone-mediated autophagy. In many cases, activation of autophagy by rapamycin is able to restore the quality control of proteins and organelles, to attenuate the accumulation of pathogenic proteins. Mechanisms of rapamycin therapeutic effects include activation of the clearance of neurons from pathogenic material and induction of both autophagosomal segregation of cellular material and the lysosomal flux by activating TFEB factor, which is the inductor of the lysosomal biogenesis. Short-term treatment with rapamycin has a positive therapeutic effect in models of acute brain injury (trauma, ischemia, hypoxia). Inhibition of neurodegeneration requires long-term therapy. Neuroprotective effect of rapamycin is higher if started at young age. Good results are achieved by prolonged treatment with rapamycin in intermittent mode.
KW - neurodegeneration
KW - neuroprotection
KW - autophagy
KW - rapamycin
KW - mTOR
KW - MOUSE MODEL
KW - IN-VITRO
KW - AUTOPHAGY INDUCTION
KW - PARKINSONS-DISEASE
KW - ALZHEIMERS-DISEASE
KW - AMYLOID-BETA
KW - NEURON DEATH
KW - MTOR
KW - INHIBITION
KW - CLEARANCE
U2 - 10.1134/S1819712418030108
DO - 10.1134/S1819712418030108
M3 - Review article
VL - 12
SP - 347
EP - 358
JO - Neurochemical Journal
JF - Neurochemical Journal
SN - 1819-7124
IS - 4
ER -
ID: 18642182