Lewy body radius growth: The hypothesis of the cube root of time dependency

Kuznetsov, Andrey V.

doi:10.1016/j.jtbi.2024.111734

Cited by 6 publications

(4 citation statements)

References 44 publications

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“…The term autocatalytic refers to the concept that early seeds of LBs further progress into mature LBs autonomously through self-assembly via the interactions of various components due to their chemical properties. In fact, as reported by recent studies [11,12], LB formation progresses up to the catalysis of early seeds, which are formed by various protein aggregates, protein-lipid aggregates, or even aggregates of membrane-bound organelles in the absence of alpha-syn fibrils [11]. Thus, one might assume that non-protein vesicular components may also be able to seed and grow step-by-step for the formation of LBs, as recently figured out by applying predictive mathematical modeling [11,12], simulated in experimental models [13,14], and confirmed in human post mortem studies [1].…”

Section: Is Alpha-syn the Natural Seed Of Lbs?supporting

confidence: 67%

“…In fact, as reported by recent studies [11,12], LB formation progresses up to the catalysis of early seeds, which are formed by various protein aggregates, protein-lipid aggregates, or even aggregates of membrane-bound organelles in the absence of alpha-syn fibrils [11]. Thus, one might assume that non-protein vesicular components may also be able to seed and grow step-by-step for the formation of LBs, as recently figured out by applying predictive mathematical modeling [11,12], simulated in experimental models [13,14], and confirmed in human post mortem studies [1]. The occurrence of abundant membranous organelles within LBs is likely to foster LB formation, even by their interaction with alphasyn [11,12].…”

Section: Is Alpha-syn the Natural Seed Of Lbs?supporting

confidence: 67%

“…In line with this, a reversed discrepancy is shown by PLA at the cortical level (crucial in DLB), where the occurrence of LB pathology is slighter compared with the severe burden of alpha-syn oligomers [98]. The inference that alpha-syn is key in forming LB was further challenged by a mathematical simulation based on updated LB composition by [11,12]. In these studies, the progression of LB could be induced by aggregates of lipid membrane-containing organelles.…”

Section: Alternative Mechanismsmentioning

confidence: 94%

“…Thus, one might assume that non-protein vesicular components may also be able to seed and grow step-by-step for the formation of LBs, as recently figured out by applying predictive mathematical modeling [11,12], simulated in experimental models [13,14], and confirmed in human post mortem studies [1]. The occurrence of abundant membranous organelles within LBs is likely to foster LB formation, even by their interaction with alphasyn [11,12]. Apart from lipid membranes, other proteins than alpha-syn are now claimed as potential seeds of LBs, which confirms that the catalytic role of alpha-syn as a building block to start neuronal inclusions is debatable [11,15,16].…”

Section: Is Alpha-syn the Natural Seed Of Lbs?mentioning

confidence: 99%

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Is There a Place for Lewy Bodies before and beyond Alpha-Synuclein Accumulation? Provocative Issues in Need of Solid Explanations

Lenzi,

Lazzeri,

Ferrucci

et al. 2024

IJMS

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In the last two decades, alpha-synuclein (alpha-syn) assumed a prominent role as a major component and seeding structure of Lewy bodies (LBs). This concept is driving ongoing research on the pathophysiology of Parkinson’s disease (PD). In line with this, alpha-syn is considered to be the guilty protein in the disease process, and it may be targeted through precision medicine to modify disease progression. Therefore, designing specific tools to block the aggregation and spreading of alpha-syn represents a major effort in the development of disease-modifying therapies in PD. The present article analyzes concrete evidence about the significance of alpha-syn within LBs. In this effort, some dogmas are challenged. This concerns the question of whether alpha-syn is more abundant compared with other proteins within LBs. Again, the occurrence of alpha-syn compared with non-protein constituents is scrutinized. Finally, the prominent role of alpha-syn in seeding LBs as the guilty structure causing PD is questioned. These revisited concepts may be helpful in the process of validating which proteins, organelles, and pathways are likely to be involved in the damage to meso-striatal dopamine neurons and other brain regions involved in PD.

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Section: Is Alpha-syn the Natural Seed Of Lbs?supporting

confidence: 67%

Section: Is Alpha-syn the Natural Seed Of Lbs?supporting

confidence: 67%

Section: Alternative Mechanismsmentioning

confidence: 94%

Section: Is Alpha-syn the Natural Seed Of Lbs?mentioning

confidence: 99%

See 2 more Smart Citations

Is There a Place for Lewy Bodies before and beyond Alpha-Synuclein Accumulation? Provocative Issues in Need of Solid Explanations

Lenzi,

Lazzeri,

Ferrucci

et al. 2024

IJMS

View full text Add to dashboard Cite

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In situ stoichiometry amounts of p62 and poly-ubiquitin exceed the increase of alpha-synuclein during degeneration of catecholamine cells induced by autophagy inhibition in vitro

Lenzi,

Lazzeri,

Ferrucci

et al. 2024

J Neural Transm

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Neurodegenerative disorders are typically featured by the occurrence of neuronal inclusions. In the case of Parkinson’s disease (PD) these correspond to Lewy bodies (LBs), which are routinely defined as proteinaceous inclusions composed of alpha-synuclein (alpha-syn). In turn, alpha-syn is considered to be the key protein in producing PD and fostering its progression. Recent studies challenged such a concept and emphasized the occurrence of other proteins such as p62 and poly-ubiquitin (Poly-ub) in the composition of LBs, which are also composed of large amounts of tubulo-vesicular structures. All these components, which accumulate within the cytosol of affected neurons in PD, may be the consequence of a dysfunction of major clearing pathways. In fact, autophagy-related systems are constantly impaired in inherited PD and genetic models of PD. The present study was designed to validate whether a pharmacological inhibition of autophagy within catecholamine cells produces cell damage and accumulation of specific proteins and tubulo-vesicular structures. The stoichiometry counts of single proteins, which accumulate within catecholamine neurons was carried out along with the area of tubulo-vesicular structures. In these experimental conditions p62 and Poly-ub accumulation exceeded at large the amounts of alpha-syn. In those areas where Poly-ub and p62 were highly expressed, tubulo-vesicular structures were highly represented compared with surrounding cytosol. The present study confirms new vistas about LBs composition and lends substance to the scenario that autophagy inhibition rather than a single protein dysfunction as key determinant of PD.

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Simulating the growth of TAF15 inclusions in neuron soma

Kuznetsov

2024

Preprint

Self Cite

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To the best of the author’s knowledge, this paper presents the first attempt to develop a mathematical model of the formation and growth of TAF15 inclusions. It has recently been shown that TAF15 inclusions are involved in approximately 10% of cases of frontotemporal lobar degeneration (FTLD). FTLD is the second most common neurodegenerative disease after Alzheimer’s disease (AD). It is characterized by a progressive loss of personality, behavioral changes, and a decline in language skills due to the degeneration of the frontal and anterior temporal lobes. The model simulates TAF15 monomer production, nucleation and autocatalytic growth of free TAF15 aggregates, and their deposition into TAF15 inclusions. The accuracy of the numerical solution of model equations is validated by comparing it with analytical solutions available for limiting cases. Physiologically relevant parameter values were used to predict TAF15 inclusion growth. It is shown that the growth of TAF15 inclusions is influenced by two opposing mechanisms: the rate at which free TAF15 aggregates are deposited into inclusions and the rate of autocatalytic production of free TAF15 aggregates from monomers. A low deposition rate slows inclusion growth, while a high deposition rate hinders the autocatalytic production of new aggregates, thus also slowing inclusion growth. Consequently, the rate of inclusion growth is maximized at an intermediate deposition rate of free TAF15 aggregates into TAF15 inclusions.

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Lewy body radius growth: The hypothesis of the cube root of time dependency

Cited by 6 publications

References 44 publications

Is There a Place for Lewy Bodies before and beyond Alpha-Synuclein Accumulation? Provocative Issues in Need of Solid Explanations

Is There a Place for Lewy Bodies before and beyond Alpha-Synuclein Accumulation? Provocative Issues in Need of Solid Explanations

In situ stoichiometry amounts of p62 and poly-ubiquitin exceed the increase of alpha-synuclein during degeneration of catecholamine cells induced by autophagy inhibition in vitro

Simulating the growth of TAF15 inclusions in neuron soma

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