Back to the tubule: microtubule dynamics in Parkinson’s disease

Pellegrini, Laura; Wetzel, Andrea; Grannò, Simone; Heaton, George R.; Harvey, Kirsten

doi:10.1007/s00018-016-2351-6

Cited by 116 publications

(107 citation statements)

References 286 publications

(395 reference statements)

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“…The staining of pSer129 + inclusions with the Proteostat aggresomal dye is consistent with previous studies on similarities between Lewy bodies and aggresomes (112,161). The formation of the aggresome is microtubule-dependent (96) and α-synuclein appears to interact with tubulin, perhaps serving as a microtubule dynamase (6,37,135). Aggresomes are hypothesized to serve as a protective mechanism facilitating cellular survival under proteotoxic conditions (162), as they are observed in 53%-60% of nonapoptotic cells but only 10%-13% of apoptotic cells in vitro (161).…”

Section: α-Synucleinopathic Inclusions In the Preformed Fibril Model supporting

confidence: 89%

The center of olfactory bulb‐seeded α‐synucleinopathy is the limbic system and the ensuing pathology is higher in male than in female mice

et al. 2019

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At early disease stages, Lewy body disorders are characterized by limbic vs. brainstem α‐synucleinopathy, but most preclinical studies have focused solely on the nigrostriatal pathway. Furthermore, male gender and advanced age are two major risk factors for this family of conditions, but their influence on the topographical extents of α‐synucleinopathy and the degree of cell loss are uncertain. To fill these gaps, we infused α‐synuclein fibrils in the olfactory bulb/anterior olfactory nucleus complex—one of the earliest and most frequently affected brain regions in Lewy body disorders—in 3‐month‐old female and male mice and in 11‐month‐old male mice. After 6 months, we observed that α‐synucleinopathy did not expand significantly beyond the limbic connectome in the 9‐month‐old male and female mice or in the 17‐month‐old male mice. However, the 9‐month‐old male mice had developed greater α‐synucleinopathy, smell impairment and cell loss than age‐matched females. By 10.5 months post‐infusion, fibril treatment hastened mortality in the 21.5‐month‐old males, but the inclusions remained centered in the limbic system in the survivors. Although fibril infusions reduced the number of cells expressing tyrosine hydroxylase in the substantia nigra of young males at 6 months post‐infusion, this was not attributable to true cell death. Furthermore, mesencephalic α‐synucleinopathy, if present, was centered in mesolimbic circuits (ventral tegmental area/accumbens) rather than within strict boundaries of the nigral pars compacta, which were defined here by tyrosine hydroxylase immunolabel. Nonprimate models cannot be expected to faithfully recapitulate human Lewy body disorders, but our murine model seems reasonably suited to (i) capture some aspects of Stage IIb of Lewy body disorders, which displays a heavier limbic than brainstem component compared to incipient Parkinson’s disease; and (ii) leverage sex differences and the acceleration of mortality following induction of olfactory α‐synucleinopathy.

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Section: α-Synucleinopathic Inclusions In the Preformed Fibril Model supporting

confidence: 89%

The center of olfactory bulb‐seeded α‐synucleinopathy is the limbic system and the ensuing pathology is higher in male than in female mice

et al. 2019

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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%

“…Low tubulin acetylation levels, along with a concomitant impairment in axonal transport, is a common pathological hallmark in several neurodegenerative diseases; the application of drugs targeting MT acetylation is considered to be a useful strategy for therapeutic intervention . Indeed, specific HDAC6 inhibitors exerted neuroprotection, rescued transport defects in some PD models . Sirtuin‐2 inhibitors also rescued SYN toxicity in different cellular and animal models of PD .…”

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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“…These data suggest a functional link between MT acetylation patterns and brain aging, evidencing how the regulation of MT stability is critical during normal neuronal aging and supporting the concept that its failure may be a reliable candidate in causing neurodegenerative processes. Indeed, during the last years, an increasing body of evidence indicated the potential role of defective regulation of MT stability in neurodegenerative disorders [18] and, in particular, in Parkinson's Disease (PD) [19,20].PD is the second most common neurodegenerative disorder caused by the death of the dopaminergic neurons in the Substantia nigra [21] whose anatomy, with an average arborisation of 4.6 meters in humans [22], makes them particularly dependant on axonal transport which, in turn, depends on MT integrity and whose failure has been associated to the early phases of PD [23]. Although the identity of the real culprit of the pathology is still debated, in the recent years it is becoming ever clearer that MT destabilization is an early event in experimental and human models of PD, and many of the studies reported below strongly suggest that it can be followed by the hyper-stabilization of MTs, which could lead to detrimental side effects.…”

mentioning

confidence: 99%

mentioning

confidence: 99%

Is the Regulation of Microtubule Stability at the Crossroad Between Aging and Disease of Dopaminergic neurons?

Cartelli¹

2017

AND

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Microtubules (MTs) are built up by αβ tubulin dimers, which assemble into non-covalent polymers with an intrinsic resistance to bending and compression and capable to alternate slow polymerizing phases to rapid shrinking ones, a behaviour called "dynamic instability" [1]. The proper regulation of MT stability (i.e., more stable MTs display a longer half-life) is fundamental for the development, the survival and the aging of neurons, since both hyper-stable and overly dynamic MTs affect neuronal functions eventually leading to cell death [2]. α and β tubulin Posttranslational Modifications (PTMs) mark dynamic or stable MTs, which are found in specific neuronal compartments and whose stability changes during neuronal differentiation and aging [3]. Indeed, tyrosinated α tubulin is associated to highly dynamic MTs, which are abundant in young neurons and at the presynaptic bouton of mature neurons. During neuronal maturation MT stability increases and MTs inside the axonal shaft accumulate PTMs which extend their half-life, either through a direct stabilization of the MT lattice [4] or by governing upstream events, such as the recruitment of MT-interacting protein [5] or by protecting MTs from depolymerizing kinesins and severing enzymes [6,7]. Nevertheless, the stability of MTs has to be maintained under a physiological threshold, since their excessive stabilization can eventually lead to MT bundling and block of axonal transport [8]. As many of the axonal MTs are long-lived polymers which persist for the entire life of the neuron, their aging is a critical event which potentially impacts on the neuron lifespan. Indeed, MTs are structures with an intrinsic self-repair capability [9] but, due to defects accumulated during growth [10] and to their ends which become more tapered during time [11], the older MTs are more susceptible to catastrophes than younger ones [12,13]. Interestingly, tubulin PTMs are potential regulators of this process as much as, for long time, acetylated MTs were referred almost synonymously to old and stable MTs. Indeed, among its several biological functions [14], it has been shown that acetylation accumulates during MT aging and it has been proposed that the MT-acetylase α Tubulin Acetyl Transferase1 (αTAT1) can act as a clock for MT lifetimes [15], due to its preference for MTs and its low catalytic rate. Nevertheless, other candidates may be responsible for minor tubulin acetylation in vivo, including Elongator Complex Protein Elp3, which acts as tubulin acetylase, controlling the development and the migration of cortical neurons [16]. Furthermore, the age-dependent decrease of the activity of sirtuin 1, a widespread deacetylase which also acts on MTs, could lead to increased acetylation of α tubulin in the cerebellum of aged mice [17]. These data suggest a functional link between MT acetylation patterns and brain aging, evidencing how the regulation of MT stability is critical during normal neuronal aging and supporting the concept that its failure may be a reliable candidate in causing n...

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Back to the tubule: microtubule dynamics in Parkinson’s disease

Cited by 116 publications

References 286 publications

The center of olfactory bulb‐seeded α‐synucleinopathy is the limbic system and the ensuing pathology is higher in male than in female mice

The center of olfactory bulb‐seeded α‐synucleinopathy is the limbic system and the ensuing pathology is higher in male than in female mice

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

Is the Regulation of Microtubule Stability at the Crossroad Between Aging and Disease of Dopaminergic neurons?

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