Effects of pharmacological modulators of α-synuclein and tau aggregation and internalization

Parkinson's disease (PD) and Alzheimer's disease (AD) are common neurodegenerative disorders of the elderly and, therefore, affect a growing number of patients worldwide. Both diseases share, as a common hallmark, the accumulation of characteristic protein aggregates, known as Lewy bodies (LB) in PD, and neurofibrillary tangles in AD. LBs are primarily composed of misfolded α-synuclein (aSyn), and neurofibrillary tangles are primarily composed of tau protein. Importantly, upon pathological evaluation, most AD and PD/Lewy body dementia cases exhibit mixed pathology, with the co-occurrence of both LB and neurofibrillary tangles, among other protein inclusions. Recent studies suggest that both aSyn and tau pathology can spread and propagate through neuronal connections. Therefore, it is important to investigate the mechanisms underlying aggregation and propagation of these proteins for the development of novel therapeutic strategies. Here, we assessed the effects of different pharmacological interventions on the aggregation and internalization of tau and aSyn. We found that anle138b and fulvic acid decrease aSyn and tau aggregation, that epigallocatechin gallate decreases aSyn aggregation, and that dynasore reduces tau internalization. Establishing the effects of small molecules with different chemical properties on the aggregation and spreading of aSyn and tau will be important for the development of future therapeutic interventions

Correction to: Pharmacological Modulators of Tau Aggregation and Spreading (<em>Brain Sciences</em>, (2020), 10, 11, (858), 10.3390/brainsci10110858)

\ua9 2024 by the authors.There was an error in the original publication [1]. References 34, 41, 52, 53, 56, 61, 64, 65, 68, 69, 71, 72, 74, 75, 76, 77, 81, 85, 86, 110, 112, and 114 were not the ones intended, and were unrelated with the main text. A correction has been made to References 34, 41, 52, 53, 56, 61, 64, 65, 68, 69, 71, 72, 74, 75, 76, 77, 81, 85, 86, 110, 112, and 114, and appear as follows: Chaudhary, A.R.; Berger, F.; Berger, C.L.; Hendricks, A.G. Tau directs intracellular trafficking by regulating the forces exerted by kinesin and dynein teams. Traffic 2018, 19, 111–121. Lim, S.; Haque, M.M.; Kim, D.; Kim, D.J.; Kim, Y.K. Cell-based Models To Investigate Tau Aggregation. Comput. Struct. Biotechnol. J. 2014, 12, 7–13. Lee, V.M.; Goedert, M.; Trojanowski, J.Q. Neurodegenerative tauopathies. Annu. Rev. Neurosci. 2001, 24, 1121–1159. Rademakers, R.; Cruts, M.; van Broeckhoven, C. The role of tau (MAPT) in frontotemporal dementia and related tauopathies. Hum. Mutat. 2004, 24, 277–295. Cowan, C.M.; Mudher, A. Are tau aggregates toxic or protective in tauopathies? Front. Neurol. 2013, 4, 114. Furcila, D.; Dom\uednguez-\uc1lvaro, M.; DeFelipe, J.; Alonso-Nanclares, L. Subregional Density of Neurons, Neurofibrillary Tangles and Amyloid Plaques in the Hippocampus of Patients With Alzheimer’s Disease. Front. Neuroanat. 2019, 13, 99. He, Z.; Guo, J.L.; McBride, J.D.; Narasimhan, S.; Kim, H.; Changolkar, L.; Zhang, B.; Gathagan, R.J.; Yue, C.; Dengler, C.; et al. Amyloid-β plaques enhance Alzheimer’s brain tau-seeded pathologies by facilitating neuritic plaque tau aggregation. Nat. Med. 2018, 24, 29–38. Park, S.; Lee, J.H.; Jeon, J.H.; Lee, M.J. Degradation or aggregation: The ramifications of post-translational modifications on tau. BMB Rep. 2018, 51, 265–273, Erratum in BMB Rep. 2020, 53, 391. Elbaum-Garfinkle, S.; Rhoades, E. Identification of an aggregation-prone structure of tau. J. Am. Chem. Soc. 2012, 134, 16607–16613. Lee, V.M.; Balin, B.J.; Otvos, L., Jr.; Trojanowski, J.Q. A68: A major subunit of paired helical filaments and derivatized forms of normal tau. Science 1991, 251, 675–678. Weissmann, C.; Reyher, H.J.; Gauthier, A.; Steinhoff, H.J.; Junge, W.; Brandt, R. Microtubule binding and trapping at the tip of neurites regulate tau motion in living neurons. Traffic 2009, 10, 1655–1668. Lathuili\ue8re, A.; Vald\ue9s, P.; Papin, S.; Cacquevel, M.; Maclachlan, C.; Knott, G.W.; Muhs, A.; Paganetti, P.; Schneider, B.L. Motifs in the tau protein that control binding to microtubules and aggregation determine pathological effects. Sci. Rep. 2017, 7, 13556. Barth\ue9lemy, N.R.; Li, Y.; Joseph-Mathurin, N.; Gordon, B.A.; Hassenstab, J.; Benzinger, T.L.; Buckles, V.; Fagan, A.M.; Perrin, R.J.; Goate, A.M.; et al. A soluble phosphorylated tau signature links tau, amyloid and the evolution of stages of dominantly inherited Alzheimer’s disease. Nat. Med. 2020, 26, 398–407. Mocanu, M.M.; Nissen, A.; Eckermann, K.; Khlistunova, I.; Biernat, J.; Drexler, D.; Petrova, O.; Sch\uf6nig, K.; Bujard, H.; Mandelkow, E.; et al. The potential for beta-structure in the repeat domain of tau protein determines aggregation, synaptic decay, neuronal loss, and coassembly with endogenous Tau in inducible mouse models of tauopathy. J. Neurosci. 2008, 28, 737–748. Olsen, M.; Aguilar, X.; Sehlin, D.; Fang, X.T.; Antoni, G.; Erlandsson, A.; Syv\ue4nen, S. Astroglial Responses to Amyloid-Beta Progression in a Mouse Model of Alzheimer’s Disease. Mol. Imaging Biol. 2018, 20, 605–614. Valotassiou, V.; Malamitsi, J.; Papatriantafyllou, J.; Dardiotis, E.; Tsougos, I.; Psimadas, D.; Alexiou, S.; Hadjigeorgiou, G.; Georgoulias, P. SPECT and PET imaging in Alzheimer’s disease. Ann. Nucl. Med. 2018, 32, 583–593. Ferrer, I.; Andr\ue9s-Benito, P.; Zelaya, M.V.; Aguirre, M.E.E.; Carmona, M.; Aus\uedn, K.; Lach\ue9n-Montes, M.; Fern\ue1ndez-Irigoyen, J.; Santamar\ueda, E.; Del Rio, J.A. Familial globular glial tauopathy linked to MAPT mutations: Molecular neuropathology and seeding capacity of a prototypical mixed neuronal and glial tauopathy. Acta. Neuropathol. 2020, 139, 735–771. Novak, P.; Cehlar, O.; Skrabana, R.; Novak, M. Tau Conformation as a Target for Disease-Modifying Therapy: The Role of Truncation. J. Alzheimers Dis. 2018, 64, S535–S546. Amadoro, G.; Latina, V.; Corsetti, V.; Calissano, P. N-terminal tau truncation in the pathogenesis of Alzheimer’s disease (AD): Developing a novel diagnostic and therapeutic approach. Biochim. Biophys. Acta. Mol. Basis Dis. 2020, 1866, 165584. Maeda, S.; Sahara, N.; Saito, Y.; Murayama, M.; Yoshiike, Y.; Kim, H.; Miyasaka, T.; Murayama, S.; Ikai, A.; Takashima, A. Granular tau oligomers as intermediates of tau filaments. Biochemistry 2007, 46, 3856–3861. Michel, C.H.; Kumar, S.; Pinotsi, D.; Tunnacliffe, A.; St George-Hyslop, P.; Mandelkow, E.; Mandelkow, E.M.; Kaminski, C.F.; Kaminski Schierle, G.S. Extracellular monomeric tau protein is sufficient to initiate the spread of tau protein pathology. J. Biol. Chem. 2014, 289, 956–967. Weaver, C.L.; Espinoza, M.; Kress, Y.; Davies, P. Conformational change as one of the earliest alterations of tau in Alzheimer’s disease. Neurobiol. Aging 2000, 21, 719–727. Chaudhary, A.R.; Berger, F.; Berger, C.L.; Hendricks, A.G. Tau directs intracellular trafficking by regulating the forces exerted by kinesin and dynein teams. Traffic 2018, 19, 111–121. Lim, S.; Haque, M.M.; Kim, D.; Kim, D.J.; Kim, Y.K. Cell-based Models To Investigate Tau Aggregation. Comput. Struct. Biotechnol. J. 2014, 12, 7–13. Lee, V.M.; Goedert, M.; Trojanowski, J.Q. Neurodegenerative tauopathies. Annu. Rev. Neurosci. 2001, 24, 1121–1159. Rademakers, R.; Cruts, M.; van Broeckhoven, C. The role of tau (MAPT) in frontotemporal dementia and related tauopathies. Hum. Mutat. 2004, 24, 277–295. Cowan, C.M.; Mudher, A. Are tau aggregates toxic or protective in tauopathies? Front. Neurol. 2013, 4, 114. Furcila, D.; Dom\uednguez-\uc1lvaro, M.; DeFelipe, J.; Alonso-Nanclares, L. Subregional Density of Neurons, Neurofibrillary Tangles and Amyloid Plaques in the Hippocampus of Patients With Alzheimer’s Disease. Front. Neuroanat. 2019, 13, 99. He, Z.; Guo, J.L.; McBride, J.D.; Narasimhan, S.; Kim, H.; Changolkar, L.; Zhang, B.; Gathagan, R.J.; Yue, C.; Dengler, C.; et al. Amyloid-β plaques enhance Alzheimer’s brain tau-seeded pathologies by facilitating neuritic plaque tau aggregation. Nat. Med. 2018, 24, 29–38. Park, S.; Lee, J.H.; Jeon, J.H.; Lee, M.J. Degradation or aggregation: The ramifications of post-translational modifications on tau. BMB Rep. 2018, 51, 265–273, Erratum in BMB Rep. 2020, 53, 391. Elbaum-Garfinkle, S.; Rhoades, E. Identification of an aggregation-prone structure of tau. J. Am. Chem. Soc. 2012, 134, 16607–16613. Lee, V.M.; Balin, B.J.; Otvos, L., Jr.; Trojanowski, J.Q. A68: A major subunit of paired helical filaments and derivatized forms of normal tau. Science 1991, 251, 675–678. Weissmann, C.; Reyher, H.J.; Gauthier, A.; Steinhoff, H.J.; Junge, W.; Brandt, R. Microtubule binding and trapping at the tip of neurites regulate tau motion in living neurons. Traffic 2009, 10, 1655–1668. Lathuili\ue8re, A.; Vald\ue9s, P.; Papin, S.; Cacquevel, M.; Maclachlan, C.; Knott, G.W.; Muhs, A.; Paganetti, P.; Schneider, B.L. Motifs in the tau protein that control binding to microtubules and aggregation determine pathological effects. Sci. Rep. 2017, 7, 13556. Barth\ue9lemy, N.R.; Li, Y.; Joseph-Mathurin, N.; Gordon, B.A.; Hassenstab, J.; Benzinger, T.L.; Buckles, V.; Fagan, A.M.; Perrin, R.J.; Goate, A.M.; et al. A soluble phosphorylated tau signature links tau, amyloid and the evolution of stages of dominantly inherited Alzheimer’s disease. Nat. Med. 2020, 26, 398–407. Mocanu, M.M.; Nissen, A.; Eckermann, K.; Khlistunova, I.; Biernat, J.; Drexler, D.; Petrova, O.; Sch\uf6nig, K.; Bujard, H.; Mandelkow, E.; et al. The potential for beta-structure in the repeat domain of tau protein determines aggregation, synaptic decay, neuronal loss, and coassembly with endogenous Tau in inducible mouse models of tauopathy. J. Neurosci. 2008, 28, 737–748. Olsen, M.; Aguilar, X.; Sehlin, D.; Fang, X.T.; Antoni, G.; Erlandsson, A.; Syv\ue4nen, S. Astroglial Responses to Amyloid-Beta Progression in a Mouse Model of Alzheimer’s Disease. Mol. Imaging Biol. 2018, 20, 605–614. Valotassiou, V.; Malamitsi, J.; Papatriantafyllou, J.; Dardiotis, E.; Tsougos, I.; Psimadas, D.; Alexiou, S.; Hadjigeorgiou, G.; Georgoulias, P. SPECT and PET imaging in Alzheimer’s disease. Ann. Nucl. Med. 2018, 32, 583–593. Ferrer, I.; Andr\ue9s-Benito, P.; Zelaya, M.V.; Aguirre, M.E.E.; Carmona, M.; Aus\uedn, K.; Lach\ue9n-Montes, M.; Fern\ue1ndez-Irigoyen, J.; Santamar\ueda, E.; Del Rio, J.A. Familial globular glial tauopathy linked to MAPT mutations: Molecular neuropathology and seeding capacity of a prototypical mixed neuronal and glial tauopathy. Acta. Neuropathol. 2020, 139, 735–771. Novak, P.; Cehlar, O.; Skrabana, R.; Novak, M. Tau Conformation as a Target for Disease-Modifying Therapy: The Role of Truncation. J. Alzheimers Dis. 2018, 64, S535–S546. Amadoro, G.; Latina, V.; Corsetti, V.; Calissano, P. N-terminal tau truncation in the pathogenesis of Alzheimer’s disease (AD): Developing a novel diagnostic and therapeutic approach. Biochim. Biophys. Acta. Mol. Basis Dis. 2020, 1866, 165584. Maeda, S.; Sahara, N.; Saito, Y.; Murayama, M.; Yoshiike, Y.; Kim, H.; Miyasaka, T.; Murayama, S.; Ikai, A.; Takashima, A. Granular tau oligomers as intermediates of tau filaments. Biochemistry 2007, 46, 3856–3861. Michel, C.H.; Kumar, S.; Pinotsi, D.; Tunnacliffe, A.; St George-Hyslop, P.; Mandelkow, E.; Mandelkow, E.M.; Kaminski, C.F.; Kaminski Schierle, G.S. Extracellular monomeric tau protein is sufficient to initiate the spread of tau protein pathology. J. Biol. Chem. 2014, 289, 956–967. Weaver, C.L.; Espinoza, M.; Kress, Y.; Davies, P. Conformational change as one of the earliest alterations of tau in Alzheimer’s disease. Neurobiol. Aging 2000, 21, 719–727. The authors state that the scientific conclusions are unaffected. This correction was approved by the Academic Editor. The original publication has also been updated

LRRK2, alpha-synuclein, and tau: partners in crime or unfortunate bystanders?

The identification of genetic forms of Parkinson's disease (PD) has tremendously expanded our understanding of the players and mechanisms involved. Mutations in the genes encoding for alpha-synuclein (aSyn), LRRK2, and tau have been associated with familial and sporadic forms of the disease. aSyn is the major component of Lewy bodies and Lewy neurites, which are pathognomonic protein inclusions in PD. Hyperphosphorylated tau protein accumulates in neurofibrillary tangles in the brains of Alzheimer's disease patients but is also seen in the brains of PD patients. LRRK2 is a complex multi-domain protein with kinase and GTPase enzymatic activity. Since aSyn and tau are phosphoproteins, we review the possible interplay between the three proteins. Understanding the interplay between LRRK2, aSyn and tau is extremely important, as this may enable the identification of novel targets and pathways for therapeutic intervention

Aging-related dysregulation of dopamine and angiotensin receptor interaction

It is not known whether the aging-related decrease in dopaminergic function leads to the aging-related higher vulnerability of dopaminergic neurons and risk for Parkinson's disease. The renin-angiotensin system (RAS) plays a major role in the inflammatory response, neuronal oxidative stress, and dopaminergic vulnerability via type 1 (AT1) receptors. In the present study, we observed a counterregulatory interaction between dopamine and angiotensin receptors. We observed overexpression of AT1 receptors in the striatum and substantia nigra of young adult dopamine D1 and D2 receptor-deficient mice and young dopamine-depleted rats, together with compensatory overexpression of AT2 receptors or compensatory downregulation of angiotensinogen and/or angiotensin. In aged rats, we observed downregulation of dopamine and dopamine receptors and overexpression of AT1 receptors in aged rats, without compensatory changes observed in young animals. L-Dopa therapy inhibited RAS overactivity in young dopamine-depleted rats, but was ineffective in aged rats. The results suggest that dopamine may play an important role in modulating oxidative stress and inflammation in the substantia nigra and striatum via the RAS, which is impaired by aging. © 2014 Elsevier Inc.Peer Reviewe

Synucleinopathies: Where we are and where we need to go

Synucleinopathies are a group of disorders characterized by the accumulation of inclusions rich in the a-synuclein (aSyn) protein. This group of disorders includes Parkinson's disease, dementia with Lewy bodies (DLB), multiple systems atrophy, and pure autonomic failure (PAF). In addition, genetic alterations (point mutations and multiplications) in the gene encoding for aSyn (SNCA) are associated with familial forms of Parkinson's disease, the most common synucleinopathy. The Synuclein Meetings are a series that has been taking place every 2 years for about 12 years. The Synuclein Meetings bring together leading experts in the field of Synuclein and related human conditions with the goal of discussing and advancing the research. In 2019, the Synuclein meeting took place in Ofir, a city in the outskirts of Porto, Portugal. The meeting, entitled "Synuclein Meeting 2019: Where we are and where we need to go", brought together &gt;300 scientists studying both clinical and molecular aspects of synucleinopathies. The meeting covered a many of the open questions in the field, in a format that prompted open discussions between the participants, and underscored the need for additional research that, hopefully, will lead to future therapies for a group of as of yet incurable disorders. Here, we provide a summary of the topics discussed in each session and highlight what we know, what we do not know, and what progress needs to be made in order to enable the field to continue to advance. We are confident this systematic assessment of where we stand will be useful to steer the field and contribute to filling knowledge gaps that may form the foundations for future therapeutic strategies, which is where we need to go. (Figure presented.).</p