TY - JOUR
T1 - Linking glycation and glycosylation with inflammation and mitochondrial dysfunction in Parkinson's disease
AU - Videira, Paula A. Q.
AU - Castro-Caldas, Margarida
N1 - info:eu-repo/grantAgreement/FCT/5876/147348/PT#
info:eu-repo/grantAgreement/FCT/5876/147258/PT#
This work was supported by Fundacao para a Ciencia e a Tecnologia (FCT), and co-financed by the ERDF under the PT2020 Partnership Agreement (POCI-01-0145-FEDER-007728).
PY - 2018/6/7
Y1 - 2018/6/7
N2 - Parkinson's disease (PD) is the second most common neurodegenerative disorder, affecting about 6.3 million people worldwide. PD is characterized by the progressive degeneration of dopaminergic neurons in the Substantia nigra pars compacta, resulting into severe motor symptoms. The cellular mechanisms underlying dopaminergic cell death in PD are still not fully understood, but mitochondrial dysfunction, oxidative stress and inflammation are strongly implicated in the pathogenesis of both familial and sporadic PD cases. Aberrant post-translational modifications, namely glycation and glycosylation, together with age-dependent insufficient endogenous scavengers and quality control systems, lead to cellular overload of dysfunctional proteins. Such injuries accumulate with time and may lead to mitochondrial dysfunction and exacerbated inflammatory responses, culminating in neuronal cell death. Here, we will discuss how PD-linked protein mutations, aging, impaired quality control mechanisms and sugar metabolism lead to up-regulated abnormal post-translational modifications in proteins. Abnormal glycation and glycosylation seem to be more common than previously thought in PD and may underlie mitochondria-induced oxidative stress and inflammation in a feed-forward mechanism. Moreover, the stress-induced post-translational modifications that directly affect parkin and/or its substrates, deeply impairing its ability to regulate mitochondrial dynamics or to suppress inflammation will also be discussed. Together, these represent still unexplored deleterious mechanisms implicated in neurodegeneration in PD, which may be used for a more in-depth knowledge of the pathogenic mechanisms, or as biomarkers of the disease.
AB - Parkinson's disease (PD) is the second most common neurodegenerative disorder, affecting about 6.3 million people worldwide. PD is characterized by the progressive degeneration of dopaminergic neurons in the Substantia nigra pars compacta, resulting into severe motor symptoms. The cellular mechanisms underlying dopaminergic cell death in PD are still not fully understood, but mitochondrial dysfunction, oxidative stress and inflammation are strongly implicated in the pathogenesis of both familial and sporadic PD cases. Aberrant post-translational modifications, namely glycation and glycosylation, together with age-dependent insufficient endogenous scavengers and quality control systems, lead to cellular overload of dysfunctional proteins. Such injuries accumulate with time and may lead to mitochondrial dysfunction and exacerbated inflammatory responses, culminating in neuronal cell death. Here, we will discuss how PD-linked protein mutations, aging, impaired quality control mechanisms and sugar metabolism lead to up-regulated abnormal post-translational modifications in proteins. Abnormal glycation and glycosylation seem to be more common than previously thought in PD and may underlie mitochondria-induced oxidative stress and inflammation in a feed-forward mechanism. Moreover, the stress-induced post-translational modifications that directly affect parkin and/or its substrates, deeply impairing its ability to regulate mitochondrial dynamics or to suppress inflammation will also be discussed. Together, these represent still unexplored deleterious mechanisms implicated in neurodegeneration in PD, which may be used for a more in-depth knowledge of the pathogenic mechanisms, or as biomarkers of the disease.
KW - Aging
KW - Glycation
KW - Glycosylation
KW - Inflammation
KW - Mitochondrial dysfunction
KW - Parkinson's disease
UR - http://www.scopus.com/inward/record.url?scp=85048250230&partnerID=8YFLogxK
U2 - 10.3389/fnins.2018.00381
DO - 10.3389/fnins.2018.00381
M3 - Review article
C2 - 29930494
AN - SCOPUS:85048250230
SN - 1662-4548
VL - 12
JO - Frontiers in Neuroscience
JF - Frontiers in Neuroscience
IS - JUN
M1 - 381
ER -