Colocalization of tau and α-synuclein epitopes in Lewy bodies. J Neuropathol Exp Neurol
The major protein constituent of Lewy bodies (LBs), the pathological hallmark of Parkinson disease and dementia with Lewy bodies, is considered to be alpha-synuclein, but other proteins, in particular the microtubule-associated protein tau, have been implicated in the pathogenesis of LBs. Tau is the major structural component of neurofibrillary tangles (NFTs). Both direct immunochemical studies of partially purified LBs and indirect immunohistochemical studies have suggested that LBs may contain tau, but most of these studies were based upon a single tau antibody, and immunologic cross-reactivity was not completely excluded. To gain insight into the relation between tau and alpha-synuclein in LBs, double immunostaining was performed in Lewy body cases with a rabbit polyclonal antibody to alpha-synuclein and a panel of monoclonal antibodies to phospho- and nonphospho-tau epitopes (Alz50, CP9, CP13, PG5, TG3, PHFI) that spanned the length of the tau molecule. Tau-immunoreactive LBs were present in the medulla in 80% of the cases, irrespective of Braak stage. All tau antibodies recognized at least some LBs, arguing against nonspecific antibody cross-reactivity. In most lesions the tau immunostaining was present at the periphery of the LB. The phospho-tau antibody, TG3, detected more LBs than any of the other tau antibodies. The proportion of LBs with tau immunoreactivity was greatest in neurons vulnerable to NETs, such as those in the locus ceruleus and basal nucleus of Meynert, and least in neurons resistant to NFTs, such as the dorsal motor nucleus of the vagus in the medulla. The present results suggest that tau may coaggregate with alpha-synuclein in LBs, especially in neuronal populations vulnerable to both NFTs and LBs.
Available from: Fumitaka Kawakami
- "In general, it has been considered that formation of LBs containing í µí»¼-Syn and aggregation of abnormal phosphorylated tau are independent mechanisms that occur in different neurodegenerative diseases. However, a previous study has demonstrated that í µí»¼-Syn and abnormal phosphorylated tau were colocalized in LBs in the brain tissue of patients with sporadic PD and DLB . More detailed studies have shown that (i) í µí»¼-Syn interacts directly with tau , (ii) the PD-linked neurotoxin 1-methyl- 4-phenylpyridinium ion (MPP + )/1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP) increases the expression of í µí»¼- Syn and the phosphorylation level of tau at Ser262, Ser396, and Ser404 in cultured neuronal cells and wild-type mice, but not in í µí»¼-Syn-knockout mice , and (iii) PKA and GSK- 3í µí»½ are the kinases responsible for í µí»¼-Syn-dependent phosphorylation of tau  . "
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ABSTRACT: There is now a considerable body of experimental evidence that Parkinson’s disease arises through physiological interaction of causative molecules, leading to tau pathology. In this review, we discuss the physiological role of α-synuclein and LRRK2 in the abnormal phosphorylation of tau. In addition, as recent reports have indicated that heat shock proteins- (HSPs-) inducing drugs can help to ameliorate neurodegenerative diseases associated with tau pathology, we also discuss therapeutic strategies for PD focusing on inhibition of α-synuclein- and LRRK2-associated tau phosphorylation by HSPs.
Available from: Victoria Zelaya
- "Double-label studies demonstrated that in Pick disease -a 3R tauopathy-, LBs usually colocalize with tau-positive Pick bodies (Popescu et al., 2004). Regarding AD cases, in which tau is composed of a mixture of 3R and 4R tau isoforms, LBs typically colocalize with tau-positive neurofibrillary tangles especially in neuronal populations vulnerable to both neurofibrillary tangles and LBs, such as those in the LC and basal nucleus of Meynert (Ishizawa et al., 2003). Moreover, a potential α-synuclein and tau co-aggregation in neurons and neuritis from the olfactory bulb in AD patients has been more recently reported (Fujishiro et al., 2008). "
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To analyze the frequency and distribution of α-synuclein deposits in progressive supranuclear palsy (PSP).
The brains of 25 cases of pathologically confirmed PSP were evaluated with immunohistochemistry for α-synuclein and tau. Multiple immunofluorescent stains were applied to analyze the expression of tau and α-synuclein aggregates in catecholaminergic neurons. Patients' clinical symptoms were retrospectively recorded.
Deposits α-synuclein in the form of typical Lewy bodies (LBs) were only found in two PSP cases (8%) that fulfilled the clinical subtype of PSP known as Richardson's syndrome (RS). LBs were present in the locus ceruleus (LC), substantia nigra pars compacta (SNc), basal forebrain, amygdala and cingulated cortex in a distribution mimicking that of Parkinson's disease (PD). Triple-immunolabeling revealed co-expression of α-synuclein and tau proteins in some tyrosine hydroxilase (TH)-positive neurons of the LC and SNc.
There is no apparent clinical correlation between the presence of LBs in PSP. Tau protein co-aggregate with α-synuclein in catecholaminergic neurons of PSP brains suggesting a synergistic interaction between the two proteins. This is in keeping with the current view of neurodegenerative disorders as "misfolded protein diseases".
Available from: Sandra Tenreiro
- "Notably, with progression of the disease , tau is phosphorylated at pathological multiple-site epitopes (AT8, AT100, AT180, PHF-1, 12E8). Tau inclusions were observed in other neurodegenerative disorders such as MSA (Giasson et al., 2003b), familial and sporadic PD (Ishizawa et al., 2003; Rajput et al., 2006), and in Down syndrome (Flament et al., 1990; Mondragon-Rodriguez et al., 2014). Elevated levels of AT180 (pT231/pS235)-phosphorylated tau were detected in the cerebrospinal fluid (CSF) of patients with mild cognitive impairment who later went on to develop AD (Arai et al., 2000a). "
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ABSTRACT: Protein misfolding and aggregation is a common hallmark in neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), and fronto-temporal dementia (FTD). In these disorders, the misfolding and aggregation of specific proteins occurs alongside neuronal degeneration in somewhat specific brain areas, depending on the disorder and the stage of the disease. However, we still do not fully understand the mechanisms governing protein aggregation, and whether this constitutes a protective or detrimental process. In PD, alpha-synuclein (aSyn) forms protein aggregates, known as Lewy bodies, and is phosphorylated at serine 129. Other residues have also been shown to be phosphorylated, but the significance of phosphorylation in the biology and pathophysiology of the protein is still controversial. In AD and in FTD, hyperphosphorylation of tau protein causes its misfolding and aggregation. Again, our understanding of the precise consequences of tau phosphorylation in the biology and pathophysiology of the protein is still limited. Through the use of a variety of model organisms and technical approaches, we are now gaining stronger insight into the effects of phosphorylation in the behavior of these proteins. In this review, we cover recent findings in the field and discuss how targeting phosphorylation events might be used for therapeutic intervention in these devastating diseases of the nervous system.
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