Acetylation as a major determinant to microtubule-dependent autophagy: Relevance to Alzheimer's and Parkinson disease pathology

Esteves, A. Raquel; Palma, A.; Gomes, Rui; Santos, Daniel; Silva, Diana F.; Cardoso, Sandra M.

doi:10.1016/j.bbadis.2018.11.014

Cited by 80 publications

(94 citation statements)

References 56 publications

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“…A number of proteins implicated in PD such as α-syn, parkin, PTEN-induced kinase 1 (PINK1), and leucine-rich repeat kinase 2 (LRRK2) have been shown to bind tubulin and regulate MT stability, highlighting the involvement of MT in the pathogenesis of this disease (Alim et al, 2004;Yang et al, 2005;Weihofen et al, 2009;Dagda et al, 2014;Godena et al, 2014;Law et al, 2014). αsyn is MT-associated protein (MAP; Esteves et al, 2019). It was demonstrated that the MT network and MT-dependent trafficking are impaired upon overexpression of α-syn (Lee et al, 2006).…”

Section: Sirt2 Decreases Microtubule Stabilitymentioning

confidence: 99%

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Emerging Role of Sirtuin 2 in Parkinson’s Disease

Liu

Zhang

Zhu

et al. 2020

Front. Aging Neurosci.

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Parkinson's disease (PD), the main risk factor of which is age, is one of the most common neurodegenerative diseases, thus presenting a substantial burden on the health of affected individuals as well as an economic burden. Sirtuin 2 (SIRT2), a subtype in the family of sirtuins, belongs to class III histone deacetylases (HDACs). It is known that SIRT2 levels increase with aging, and a growing body of evidence has been accumulating, showing that the activity of SIRT2 mediates various processes involved in PD pathogenesis, including aggregation of α-synuclein (α-syn), microtubule function, oxidative stress, inflammation, and autophagy. There have been conflicting reports about the role of SIRT2 in PD, in that some studies indicate its potential to induce the death of dopaminergic (DA) neurons, and that inhibition of SIRT2 may, therefore, have protective effects in PD. Other studies suggest a protective role of SIRT2 in the context of neuronal damage. As current treatments for PD are directed at alleviating symptoms and are very limited, a comprehensive understanding of the enzymology of SIRT2 in PD may be essential for developing novel therapeutic agents for the treatment of this disease. This review article will provide an update on our knowledge of the structure, distribution, and biological characteristics of SIRT2, and highlight its role in the pathogenesis of PD.

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Section: Sirt2 Decreases Microtubule Stabilitymentioning

confidence: 99%

“…Consequently, by inhibiting SIRT2 activity, the levels of acetylated α-tubulin are increased, thereby improving MT dynamics via enhanced α-syn/tubulin binding. The activation of SIRT2 or HDAC6 could increase the tubulin deacetylation and induce MT loss stability and depolymerization (Esteves et al, 2019).…”

Section: Sirt2 Decreases Microtubule Stabilitymentioning

confidence: 99%

Emerging Role of Sirtuin 2 in Parkinson’s Disease

Liu

Zhang

Zhu

et al. 2020

Front. Aging Neurosci.

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“…Alterations in the acetylation levels of nonhistone proteins, mainly α-tubulin at K40, contribute to the pathogenesis of PD caused by genetic factors such as α-syn, LRRK2, Parkin, and ATP13A2 [ 27 , 28 , 53 , 54 , 65 ]. These alterations mainly involve changes in the activity or protein levels of SIRT2 and HDAC6, two cytoplasmic KDACs ( Figure 3 A).…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, α-syn also has an inhibitory effect on the acetylation of α-tubulin via a SIRT2-related mechanism, impairing microtubule (MT) stability and contributing to PD pathology ( Figure 3 A), and the SIRT2 inhibitor AK-1 partially reverses the reduction in acetylation of α-tubulin mediated by α-syn and restores MT stability [ 65 ]. In addition, deacetylated α-tubulin interacts with α-syn oligomers to form a toxic complex [ 105 ].…”

Section: Lysine Acetylation Of Nonhistone Proteins In Pd Pathogenementioning

confidence: 99%

Imbalance of Lysine Acetylation Contributes to the Pathogenesis of Parkinson’s Disease

Wang

Sun

Wang

et al. 2020

IJMS

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Parkinson’s disease (PD) is one of the most common neurodegenerative disorders. The neuropathological features of PD are selective and progressive loss of dopaminergic neurons in the substantia nigra pars compacta, deficiencies in striatal dopamine levels, and the presence of intracellular Lewy bodies. Interactions among aging and genetic and environmental factors are considered to underlie the common etiology of PD, which involves multiple changes in cellular processes. Recent studies suggest that changes in lysine acetylation and deacetylation of many proteins, including histones and nonhistone proteins, might be tightly associated with PD pathogenesis. Here, we summarize the changes in lysine acetylation of both histones and nonhistone proteins, as well as the related lysine acetyltransferases (KATs) and lysine deacetylases (KDACs), in PD patients and various PD models. We discuss the potential roles and underlying mechanisms of these changes in PD and highlight that restoring the balance of lysine acetylation/deacetylation of histones and nonhistone proteins is critical for PD treatment. Finally, we discuss the advantages and disadvantages of different KAT/KDAC inhibitors or activators in the treatment of PD models and emphasize that SIRT1 and SIRT3 activators and SIRT2 inhibitors are the most promising effective therapeutics for PD.

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“…Destabilization of the MT network and defective interplay among cytoskeletal components has been observed in PD and other neurological disorders, as well as in cancer and inflammation . Drug‐like agents that modulate MT stability or inhibit post‐translational modifiers affecting the levels of tubulin acetylation constitute the most addressed therapeutic interventions aiming to prevent cytoskeletal damage in neurodegenerative disorders . MT stabilizers such as epithilone D displayed beneficial effects in some PD model .…”

Section: Tppp/p25: the New Hallmark Of Parkinsonismmentioning

confidence: 99%

Pharmacological targeting of α‐synuclein and TPPP/p25 in Parkinson's disease: challenges and opportunities in a Nutshell

Oláh

Ovádi

2019

FEBS Letters

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With the aging of population, neurological disorders, and especially disorders involving defects in protein conformation (also known as proteopathies) pose a serious socio‐economic problem. So far there is no effective treatment for most proteopathies, including Parkinson's disease (PD). The mechanism underlying PD pathogenesis is largely unknown, and the hallmark proteins, α‐synuclein (SYN) and tubulin polymerization promoting protein (TPPP/p25) are challenging drug targets. These proteins are intrinsically disordered with high conformational plasticity, and have diverse physiological and pathological functions. In the healthy brain, SYN and TPPP/p25 occur in neurons and oligodendrocytes, respectively; however, in PD and multiple system atrophy, they are co‐enriched and co‐localized in both cell types, thereby marking pathogenesis. Although large inclusions appear at a late disease stage, small, soluble assemblies of SYN promoted by TPPP/p25 are pathogenic. In the light of these issues, we established a new innovative strategy for the validation of a specific drug target based upon the identification of contact surfaces of the pathological SYN‐TPPP/p25 complex that may lead to the development of peptidomimetic foldamers suitable for pharmaceutical intervention.

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Acetylation as a major determinant to microtubule-dependent autophagy: Relevance to Alzheimer's and Parkinson disease pathology

Cited by 80 publications

References 56 publications

Emerging Role of Sirtuin 2 in Parkinson’s Disease

Emerging Role of Sirtuin 2 in Parkinson’s Disease

Imbalance of Lysine Acetylation Contributes to the Pathogenesis of Parkinson’s Disease

Pharmacological targeting of α‐synuclein and TPPP/p25 in Parkinson's disease: challenges and opportunities in a Nutshell

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