On the key role played by altered protein conformation in Parkinson’s disease

Abstract

On the basis of the previously proposed hierarchic organisation of the central nervous system (CNS) and of its syntropic behaviour, a view of neurodegenerative diseases focusing on the assemblage of abnormal multimeric proteins (pathologic protein mosaics (PMs)) is proposed. Thus, the main focus of the present paper is on Parkinson's disease (PD) as a neurodegenerative disease, which has as crucial feature protein conformational alterations and formation of pathological PMs. Two interconnected cellular dysfunctions are discussed as main pathogenic factors of PD syndromes, namely mitochondrial deficits (i.e. energy failure, especially critical for Substantia Nigra DA neurons) and conformational protein alterations (due to genetic or environmental causes). Conformational protein alterations can trigger pathological phenomena via the loss and/or the gain of new functions. In particular, altered proteins can lead to the formation of abnormal PMs, which can, inter alia, cause distortion of cellular structures, toxic functions and/or formation of improper membrane ion channels. In view of the fact that disordered proteins can easily acquire unwanted conformation, the "disorder index" (DI) for proteins involved in PD has been evaluated. It has been found that both alpha-synuclein and tau-protein have high DI. This datum is in agreement with the observation that these two proteins synergistically promote polymerisation of each other into amyloid fibrils, favouring the formation of Lewy bodies.

Neurotrophic factors and Parkinson's disease

“…In vitro, CDNF protein was unable to promote the survival of embryonic motor neurons or dorsal root ganglion (DRG) neurons, or early postnatal sympathetic cervical ganglion (SCG) neurons differently from GDNF that supports the survival of different neuronal populations including motoneurons and enteric, sensory, parasympathetic, and sympathetic neurons. Similar to the results obtained with CDNF were also reported for the MANF protein, although MANF showed a small survival promoting effect on DRG neurons [38].…”

A New Hypothesis of Pathogenesis Based on the Divorce between Mitochondria and their Host Cells: Possible Relevance for Alzheimers Disease

“…This protein conformational alteration appears to be correlated with reduced electron transfer rates, suggesting that excessive oxidative damage of complex I subunits leads to a misassembled complex I, hence to a pathologic Protein Mosaic [80][81][82]. This proposal is in agreement with the view that the formation of abnormal Protein Mosaics can cause distortion of cellular structures, toxic functions, and/or formation of improper membrane ion channels [81].…”

“…It should also be mentioned that these neurons are autonomous pacemaker neurons, and that this pacemaking activity depends on Ca 2+ channels (L-type Cav1.3). This task is also likely to create a metabolic stress and an additional burden upon mitochondria [81,82,84].…”

Alpha-synuclein immunopositive aggregates in the myenteric plexus of the aging Fischer 344 rat

“…In fact, an important role for alpha-synuclein in the aging of the enteric and autonomic circuitry of the GI tract might be anticipated because, in contrast to most neural systems where alpha-synuclein expression is restricted to presynaptic terminals (Andringa et al, 2003; Bennett, 2005; Halliday and McCann, 2008; Jakes et al, 1994), alpha-synuclein in the GI tract is expressed--in addition to presynaptic terminals--in the cytoplasm of neuronal somata and the axoplasm of neurites (Andringa et al, 2003; Bloch et al, 2006; Braak et al, , 2006, 2007; Hawkes et al, 2007; Miwa et al, 2006; Phillips and Powley, 2007; Phillips et al, 2008; Wakabayashi et al, 2007). Furthermore, alpha-synuclein has a tendency to fibrillize with itself and other native proteins, including tau (a protein frequently found to accumulate in aging and degenerating axons), it has a propensity to form insoluble intracellular aggregates, and it is prominently involved in synucleinopathies that frequently occur in old age (Agnati et al, 2008; Bennett, 2005; Frasier and Wolozin, 2004; Galpern and Lang, 2006; Goedert, 1999; Halliday and McCann, 2008; Lee, 2008; Mattson and Magnus, 2006), all of which make it a strong candidate to be involved in the formation of age-related inclusions in the gut’s nervous system. Finally, limited observations already indicate that at least some markedly swollen axons in the wall of the GI tract are immunopositive for alpha-synuclein (Phillips and Powley, 2007; Phillips et al, 2008), affirming the need for a more thorough examination of the expression of alpha-synuclein in the heteroplastic autonomic axons in the aging GI tract.…”