Title:Novel Molecular Targets and Mechanisms for Neuroprotective Modulation
in Neurodegenerative Disorders
Volume: 22
Issue: 2
Author(s): Aala Azari, Amin Goodarzi, Behrouz Jafarkhani, Mohammad Eghbali, Zohreh Karimi, Seyed Sajad Hosseini Balef and Hamid Irannejad*
Affiliation:
- Department of Medicinal Chemistry, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran
Keywords:
Neuroprotection, α-synuclein, ubiquitin-proteasome system, PROTAC, heat shock protein, autophagy, epigenetics.
Abstract:
Background: Neuronal death underlies the symptoms of several human neurological
disorders, including Alzheimer's, Parkinson's and Huntington's diseases, and amyotrophic lateral
sclerosis and their precise pathophysiology have not yet been elucidated. According to various
studies, the prohibition is the best therapy with neuroprotective approaches, which are advanced
and safe methods.
Methods: This review summarizes some of the already-known and newly emerged neuroprotective
targets and strategies and their experimental effects have also been reported. Accordingly, literature
was studied from 2000 to 2021, and appropriate articles were searched in Google Scholar and
Scopus with the keywords given in the keywords section of the current review.
Results: Lewy bodies are the histopathologic characteristics of neurodegenerative disorders and
are protein-rich intracellular deposits in which Alpha-synuclein is its major protein. Alphasynuclein’s
toxic potential provides a compelling rationale for therapeutic strategies aimed at decreasing
its burden in neuronal cells through numerous pathways, including ubiquitin-proteasome
system and autophagy-lysosome pathway, proteolytic breakdown via cathepsin D, kallikrein-6
(neurosin), calpain-1 or MMP9, heat shock proteins, and proteolysis targeting chimera which consists
of a target protein-ligand and an E3 ubiquitin ligase (E3) followed by target protein ubiquitination
(PROTACs). Other targets that have been noticed recently are the mutant huntingtin, tau
proteins and glycogen synthase kinase 3β; their accumulation proceeds extensive neuronal damage
and up to the minute approach such as proteolysis targeting chimera promotes its degradation in
cells. Various studies demonstrated that Mendelian gene mutations can result in neurodegenerative
diseases. An additional target that has gained much interest is epigenetics, such as mutation, phosphodiesterase,
RNA binding proteins and Nuclear respiratory factor 1.
Conclusion: The novel molecular targets and new strategies compiled and introduced here can be
used by scientists to design and discover more efficient small molecule drugs against neurodegenerative
diseases. And also, the genes in which their mutations can lead to the α-synuclein aggregation
or accumulation have been discussed and considered a valuable information on epigenetics in
dementia.
