Neuroinflammation represents a common theme amongst genetic and environmental risk factors for Alzheimer and Parkinson diseases

Journal of Neuroinflammation, Год журнала: 2022, Номер 19(1)

Опубликована: Сен. 8, 2022

Multifactorial diseases are characterized by inter-individual variation in etiology, age of onset, and penetrance. These tend to be relatively common arise from the combined action genetic environmental factors; however, parsing convoluted mechanisms underlying these gene-by-environment interactions presents a significant challenge their study management. For neurodegenerative disorders, resolving this is imperative, given enormous health societal burdens they impose. The which effects may act concert destabilize homeostasis elevate risk has become major research focus disease. Emphasis further being placed on determining extent unifying biological principle account for progressively diminishing capacity system buffer disease phenotypes, as increases. Data emerging studies common, providing insights pragmatically connect that previously seemed disparate. In review, we discuss evidence positing inflammation homeostatic destabilization affecting risk, progression diseases. Specifically, how associated with Alzheimer Parkinson contribute pro-inflammatory responses, such predisposition exacerbated insults, theme leveraged ongoing search effective therapeutic interventions.

Язык: Английский

---

Aggregation of Disordered Proteins Associated with Neurodegeneration

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(4), С. 3380 - 3380

Опубликована: Фев. 8, 2023

Cellular deposition of protein aggregates, one the hallmarks neurodegeneration, disrupts cellular functions and leads to neuronal death. Mutations, posttranslational modifications, truncations are common molecular underpinnings in formation aberrant conformations that seed aggregation. The major proteins involved neurodegeneration include amyloid beta (Aβ) tau Alzheimer’s disease, α-synuclein Parkinson’s TAR DNA-binding (TDP-43) amyotrophic lateral sclerosis (ALS). These described as intrinsically disordered possess enhanced ability partition into biomolecular condensates. In this review, we discuss role misfolding aggregation neurodegenerative diseases, specifically highlighting implications changes primary/secondary (mutations, truncations) quaternary/supramolecular (oligomerization condensation) structural landscapes for four aforementioned proteins. Understanding these mechanisms provides insights diseases their underlying pathology.

Язык: Английский

---

Role of α-synuclein in microglia: autophagy and phagocytosis balance neuroinflammation in Parkinson’s disease

Inflammation Research, Год журнала: 2023, Номер 72(3), С. 443 - 462

Опубликована: Янв. 4, 2023

Язык: Английский

---

The role of neuroimaging in Parkinson’s disease

Journal of Neurochemistry, Год журнала: 2021, Номер 159(4), С. 660 - 689

Опубликована: Сен. 17, 2021

Abstract Parkinson's disease (PD) is a neurodegenerative disorder that affects millions of people worldwide. Two hallmarks PD are the accumulation alpha‐synuclein and loss dopaminergic neurons in brain. There no cure for PD, all existing treatments focus on alleviating symptoms. diagnosis also based symptoms, such as abnormalities movement, mood, cognition observed patients. Molecular imaging methods magnetic resonance (MRI), single‐photon emission computed tomography (SPECT), positron (PET) can detect objective alterations neurochemical machinery brain help diagnose study diseases. This review addresses application functional MRI, PET, SPECT We provide an overview targets, discuss rationale behind target selection, agents (tracers) with which be performed, main findings regarding each target's state PD. has proven itself effective supporting clinical helped reveal heterogeneous disorder, important implications development future therapies. However, molecular early or differentiation between atypical parkinsonisms remained challenging. The final section dedicated to new targets one PD‐related pathological changes upstream from degeneration. foremost those alpha‐synuclein. progress tracer achieved so far challenges path toward humans. image

Язык: Английский

---

The Endoplasmic Reticulum Stress/Unfolded Protein Response and Their Contributions to Parkinson’s Disease Physiopathology

Cells, Год журнала: 2020, Номер 9(11), С. 2495 - 2495

Опубликована: Ноя. 17, 2020

Parkinson’s disease (PD) is a multifactorial age-related movement disorder in which defects of both mitochondria and the endoplasmic reticulum (ER) have been reported. The unfolded protein response (UPR) has emerged as key cellular dysfunction associated with etiology disease. UPR involves coordinated initiated that grants correct folding proteins. This review gives insights on ER its functioning; signaling cascades; link between stress, activation, physiopathology PD. Thus, post-mortem studies data obtained by either vitro vivo pharmacological approaches or genetic modulation PD causative genes are described. Further, we discuss relevance impact to sporadic pathology.

Язык: Английский

---

PARK Genes Link Mitochondrial Dysfunction and Alpha-Synuclein Pathology in Sporadic Parkinson’s Disease

Frontiers in Cell and Developmental Biology, Год журнала: 2021, Номер 9

Опубликована: Июль 6, 2021

Parkinson’s disease (PD) is an age-related neurodegenerative disorder affecting millions of people worldwide. The characterized by the progressive loss dopaminergic neurons and spread Lewy pathology (α-synuclein aggregates) in brain but pathogenesis remains elusive. PD presents substantial clinical genetic variability. Although its complex etiology has hampered breakthrough targeting modification, recent tools advanced our approaches. As such, mitochondrial dysfunction been identified as a major pathogenic hub for both familial sporadic PD. In this review, we summarize effect mutations 11 PARK genes ( SNCA, PRKN, PINK1, DJ-1, LRRK2, ATP13A2, PLA2G6, FBXO7, VPS35, CHCHD2 , VPS13C ) on function well their relevance formation pathology. Overall, these play key roles homeostatic control (biogenesis mitophagy) functions (e.g., energy production oxidative stress), which may crosstalk with autophagy pathway, induce proinflammatory immune responses, increase stress that facilitate aggregation α-synuclein. Thus, rectifying dysregulation represents promising therapeutic approach neuroprotection

Язык: Английский

---

Cross-talks among GBA mutations, glucocerebrosidase, and α-synuclein in GBA-associated Parkinson’s disease and their targeted therapeutic approaches: a comprehensive review

Translational Neurodegeneration, Год журнала: 2021, Номер 10(1)

Опубликована: Янв. 15, 2021

Current therapies for Parkinson's disease (PD) are palliative, of which the levodopa/carbidopa therapy remains primary choice but is unable to modulate progression neurodegeneration. Due complication such a multifactorial disorder and significant limitations therapy, numerous genetic approaches have been proved effective in finding out genes mechanisms implicated this disease. Following observation higher frequency PD Gaucher's (GD), lysosomal storage condition, mutations glycosylceramidase beta (GBA) encoding glucocerebrosidase (GCase) shown be involved explored context PD. GBA most common risk factor Various studies revealed relationships between gene mutations, facilitating better understanding disorder. hypotheses delineate that pathological minimize enzymatic activity GCase, affects proliferation clearance α-synuclein; homeostasis, exacerbating endoplasmic reticulum stress or encouraging mitochondrial dysfunction. Identification underlying GBA-associated parkinsonism (GBA + PD) advances our This review based on current literature aims elucidate various clinical characteristics correlated with identify processes We also therapeutic strategies interfere mutant GCase function further improvement related α-synuclein-GCase crosstalks. Moreover, as chaperone proteins, histone deacetylase inhibitors treatment discussed.

Язык: Английский

---

Protein interaction networks in neurodegenerative diseases: From physiological function to aggregation

Journal of Biological Chemistry, Год журнала: 2022, Номер 298(7), С. 102062 - 102062

Опубликована: Май 25, 2022

The accumulation of protein inclusions is linked to many neurodegenerative diseases that typically develop in older individuals, due a combination genetic and environmental factors. In rare familial disorders, genes encoding for aggregation-prone proteins are often mutated. While the underlying mechanism leading these still remains be fully elucidated, efforts past 20 years revealed vast network protein–protein interactions play major role regulating aggregation key associated with neurodegeneration. Misfolded can oligomerize form insoluble aggregates associate molecular chaperones other elements proteolytic machineries frontline workers attempting protect cells by promoting clearance preventing aggregation. Proteins normally bound become sequestered mislocalized inclusions, their loss function. contrast, mutations, posttranslational modifications, or misfolding lead gain function inducing novel altered interactions, which turn impact numerous essential cellular processes organelles, such as vesicle trafficking mitochondria. This review examines our current knowledge involving several Alzheimer's disease, Parkinson's Huntington's amyotrophic lateral sclerosis. We aim provide an overview interaction networks central driving mitigating inclusion formation, while highlighting some proteomic studies helped uncover extent networks. Neurodegenerative (NDs) complex multifactorial pathology, result progressive damage neuronal connectivity, ultimately impaired mobility and/or cognition. Protein oligomerization gives rise extracellular intracellular common hallmark NDs. Further spreading amyloid nervous system–similar prion-based infections, hence referred prion-like mechanism–is thought element etiology NDs (1Goedert M. NEURODEGENERATION. diseases: prion concept relation assembled Abeta, tau, alpha-synuclein.Science. 2015; 349: 1255555Crossref PubMed Scopus (552) Google Scholar). few decades, biochemical causes were uncovered, distinction between rarer forms, where disease-causing mutations genetically inherited, more sporadic risk factors drive pathogenesis (2Bertram L. Tanzi R.E. epidemiology disease.J. Clin. Invest. 2005; 115: 1449-1457Crossref (444) both cases, affected found enriched pathological aggregates, highlights importance manifestation disease. However, despite accumulated clinical trials attempts made alleviate aggregation, date no therapeutic strategy has been broadly accepted cure any led scientists question whether really ND mere (3Walsh D.M. Selkoe D.J. A critical appraisal pathogenic spread hypothesis neurodegeneration.Nat. Rev. Neurosci. 2016; 17: 251-260Crossref (189) Scholar, 4Makin S. on trial.Nature. 2018; 559: S4-S7Crossref Nonetheless, collectively, work decades generated understanding how each engages pathways. this review, we intricate connections bringing together core findings recent discoveries.For ND, different sets mutated brain regions cell types initially affected. For example, disease (HD) spinocerebellar ataxia type 1 (SCA1) expansion CAG repeat huntingtin (HTT) ataxin (ATXN1) genes, respectively, resulting unusually long polyglutamine (polyQ) tract very prone deposits striatal neurons (5Ross C.A. Tabrizi S.J. disease: from treatment.Lancet Neurol. 2011; 10: 83-98Abstract Full Text PDF (1062) 6Orr H.T. Zoghbi H.Y. SCA1 genetics: history 13 year collaboration against glutamines.Hum. Mol. Genet. 2001; 2307-2311Crossref (AD), two observed. aberrant cleavage products transmembrane amyloid-β (Aβ) precursor (APP) plaque temporal parietal regions, tau (MAPT) accumulates intracellularly, neurofibrillary tangles (7Selkoe Hardy J. at 25 years.EMBO Med. 8: 595-608Crossref (2881) Parkinsonś (PD), primarily area substantia nigra (SN), α-synuclein (α-syn; SNCA) accumulate dopaminergic (8Poewe W. Seppi K. Tanner C.M. Halliday G.M. Brundin P. Volkmann et al.Parkinson disease.Nat. Dis. Primers. 2017; 3: 17013Crossref (1086) ALS, superoxide dismutase (SOD1), RNA-binding FUS (FUsed Sarcoma), TAR-DNA–binding 43 (TDP-43) have identified motor primary cortex, brainstem, spinal cord (9Foerster B.R. Welsh R.C. Feldman E.L. neuroimaging sclerosis.Nat. 2013; 9: 513-524Crossref (49) It therefore important consider independently context most Note, will mostly use short names whenever gene corresponding italicized name also indicated brackets if it name.Protein disease-associated facilitated posttranslation modifications (e.g., phosphorylation cleavage) avert formation native structure, cases seemingly occur sporadically, without yet clear explanation. Aggregation first initiated seed or/and oligomer, sequence-specific misfolded interact adopt non-native conformation, then convert into toxic form. leads fibrils distinctive β-sheet structure arise when soluble oligomers begin assemble small protofibrils (10Iadanza M.G. Jackson M.P. Hewitt E.W. Ranson N.A. Radford S.E. new era structures Cell Biol. 19: 755-773Crossref (0) When converted longer larger visible light microscopy. Recently, proposed may favored liquid–liquid phase separation (11Mathieu C. Pappu R.V. Taylor J.P. Beyond aggregation: transitions disease.Science. 2020; 370: 56-60Crossref (78) Scholar) (Box 1). Moreover, now evident there polymorphs vitro vivo (polymorph term used indicate capacity polypeptide generate structures) (12Petkova A.T. Leapman R.D. Guo Z. Yau W.M. Mattson Tycko R. Self-propagating, molecular-level polymorphism beta-amyloid fibrils.Science. 307: 262-265Crossref (1401) 13Fitzpatrick A.W.P. Falcon B. He Murzin A.G. Murshudov G. Garringer H.J. al.Cryo-EM filaments disease.Nature. 547: 185-190Crossref (932) Scholar).Box 1Liquid–liquid separationConventional mechanisms disease-related proceed through oligomerization. increasing attention given (LLPS) process. Phase-separated droplets concentrated environment process accelerated. LLPS occurs molecules solution stronger than entropic cost demixing overcome condensed formed (393Banani S.F. Lee H.O. Hyman A.A. Rosen M.K. Biomolecular condensates: organizers biochemistry.Nat. 18: 285-298Crossref (1864) Beginning P granules, membraneless organelles (MLOs) shown exhibit liquid-like properties exchanging components surrounding environment, deforming under sheer force fusing (394Brangwynne C.P. Eckmann C.R. Courson D.S. Rybarska A. Hoege Gharakhani al.Germline granules liquid localize controlled dissolution/condensation.Science. 2009; 324: 1729-1732Crossref (1339) 395Weber S.C. Brangwynne Inverse size scaling nucleolus concentration-dependent transition.Curr. 25: 641-646Abstract (168) 396Wippich F. Bodenmiller Trajkovska Wanka Aebersold Pelkmans Dual specificity kinase DYRK3 couples stress granule condensation/dissolution mTORC1 signaling.Cell. 152: 791-805Abstract (351) MLOs LLPS. crucial processes, changes phase-separated ability separate emerging property proteins. Over time, separated mature solid, glass-like states (397Shin Y. Berry Pannucci N. Haataja Toettcher J.E. Spatiotemporal control using light-activated optoDroplets.Cell. 168: 159-171.e114Abstract (356) vitrified state consists thioflavin-positive discussed here. Phase presence polyanionic T-cell antigen (TIA1) (398Ambadipudi Biernat Riedel D. Mandelkow E. Zweckstetter Liquid-liquid microtubule-binding repeats Alzheimer-related Tau.Nat. Commun. 275Crossref (309) 399Ash P.E.A. Lei Shattuck Boudeau Carlomagno Medalla al.TIA1 potentiates promotes generation oligomeric tau.Proc. Natl. Acad. Sci. U. 2021; 118e2014188118Crossref (22) Phosphorylation promote its accelerate conversion solid eventually forming thioflavin-T–positive 400Wegmann Eftekharzadeh Tepper Zoltowska K.M. Bennett Dujardin al.Tau liquid-liquid initiate aggregation.EMBO 37e98049Crossref (369) 401Boyko Surewicz W.K. Regulatory fibrillation conditions separation.Proc. 117: 31882-31890Crossref (27) phase-separation α-syn requires nonphysiological periods time (402Sawner A.S. Ray Yadav Mukherjee Panigrahi Poudyal al.Modulating alpha-synuclein separation.Biochemistry. 60: 3676-3696Crossref (7) localizes negatively charged C-terminal domain positively proline-rich region (403Siegert Rankovic Favretto Ukmar-Godec T. Strohaker Becker al.Interplay separation.Protein 30: 1326-1336Crossref (11) link neurodegeneration particularly case implicated. MLOs, structural intrinsically disorder (IDRs) granules. IDRs RNA influence morphology dynamics protein–RNA (404Boeynaems Holehouse Weinhardt V. Kovacs Van Lindt Larabell al.Spontaneous forces give protein-RNA condensates coexisting phases material properties.Proc. 2019; 116: 7889-7898Crossref (174) ALS-associated low-complexity domains FUS, TIA1, heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1), TDP-43 transition (405Murakami Qamar Lin J.Q. Schierle G.S. Rees Miyashita al.ALS/FTD mutation-induced reversible hydrogels irreversible impairs RNP function.Neuron. 88: 678-690Abstract (465) 406Patel Jawerth Maharana Jahnel Hein M.Y. al.A liquid-to-solid ALS accelerated mutation.Cell. 162: 1066-1077Abstract (1272) 407Lin Protter Parker maturation proteins.Mol. Cell. 208-219Abstract (835) 408Molliex Temirov Coughlin Kanagaraj A.P. Kim al.Phase low complexity assembly drives fibrillization.Cell. 163: 123-133Abstract (1219) 409Conicella A.E. Zerze G.H. Mittal Fawzi N.L. disrupt mediated alpha-helical domain.Structure. 24: 1537-1549Abstract (382) 410Mackenzie I.R. Nicholson A.M. Sarkar Messing Purice M.D. Pottier sclerosis frontotemporal dementia alter dynamics.Neuron. 95: 808-816.e809Abstract (328) These pathology disrupting functions trapping translational machinery Low-complexity characteristic HTT separates weak hydrophobic polyQ (411Peskett T.R. Rau O'Driscoll Patani Lowe A.R. Saibil H.R. Exon1 aggregation.Mol. 70: 588-601.e586Abstract (130) 412Aktar Burudpakdee Polanco Pei Swayne T.C. Lipke P.N. al.The dynamic compartment.Life Alli. 2e201900489PubMed With length, quickly lower concentration. structures. Interestingly, profilin interacts reduces separate, well reduced rate fibril (413Posey Ruff Harmon T.S. Crick S.L. Li Diamond M.I. al.Profilin N-terminal fragments preferentially binding monomers oligomers.J. Chem. 293: 3734-3746Abstract (61) PPIs behavior intertwined potentially neurodegeneration.Protein cause series deleterious events cell. First, aggregated affect (PPIs) natively folded protein. interacting coaggregate. later, main known briefly discuss physiological relevance. underline disease-specific PPIs, especially aggregation.In addition, species mediate engage would not (14Schaefer M.H. Wanker E.E. Andrade-Navarro M.A. Evolution CAG/polyglutamine protein-protein networks.Nucl. Acids Res. 2012; 40: 4273-4287Crossref Notably, acute chronic exposure unraveling buried, hydrophobic, even unrelated proteins, thereby coaggregation polypeptides (15Olzscha H. Schermann S.M. Woerner A.C. Pinkert Hecht Tartaglia G.G. al.Amyloid-like sequester metastable functions.Cell. 144: 67-78Abstract (496) gained perturb normal instance, all reviewed form, mitochondrial disrupted perturbations detail chapter centrality ND. addition interfering membranes, exacerbate cytotoxicity 16Kayed Head Thompson J.L. McIntire T.M. Milton Cotman C.W. al.Common implies pathogenesis.Science. 2003; 300: 486-489Crossref (3379) As aggregating arranged polymorphs, differentially, depending propagate components. dictate conformation favored, could (17Peng Gathagan R.J. Covell Medellin Stieber Robinson al.Cellular milieu imparts distinct strains alpha-synucleinopathies.Nature. 557: 558-563Crossref (288) Scholar).To deal challenges posed human developed coping largely rely homeostasis network. Molecular maintain (a.k.a. proteostasis) facilitating folding disaggregation, targeting degradation (18Klaips C.L. Jayaraj Hartl F.U. Pathways proteostasis aging 217: 51-63Crossref (337) Different pathways eliminate directing them either ubiquitin–proteasome lysosomal system. Furthermore, displays protective noncytotoxic, less toxic, lowering smaller via sequestration (19Lansbury P.T. Lashuel H.A. century-old debate enters clinic.Nature. 2006; 443: 774-779Crossref Nevertheless, described previously extend quality itself. effects reducing pool available functions, impairing proteasome exacerbating (20Keck Nitsch Grune Ullrich O. Proteasome inhibition paired helical filament-tau brains patients Neurochem. 85: 115-122Crossref 21Guo Q. Lehmer Martinez-Sanchez Rudack Beck Hartmann al.In Situ C9orf72 poly-GA reveals recruitment.Cell. 172: 696-705.e612Abstract (201) Understanding during progression reveal strategies treatment NDs.The functional characterization so far proven challenge. elucidated. contributing modifiers ND-causing poorly understood. Few systematically analyzed similarities causing Therefore, decided work, interrogating PPI (PINs) around carefully examining mitochondria, order general view determine commonalities diseases.Building networksIdentification was guided initial immunochemistry. elucidation targeted approaches—customarily assessing coimmunoprecipitation—still represents large portion related unbiased searches better partners driven yeast two-hybrid (Y2H) method, technique emerged over ago. Advances identification methodologies 2 including improvement mass spectrometry instrumentation, further unraveled PINs, providing additional insights involved Major contributions PINs come proteomics coimmunoprecipitation experiments, commonly affinity purification (AP-MS) 2), proximity-labeling approaches 3) becoming increasingly popular.Box 2Affinity spectrometryAffinity refers enrichment isolation particular (i.e., bait) prey) method (414Gingras Gstaiger Raught Analysis complexes spectrometry.Nat. 2007; 645-654Crossref (540) 415Smits A.H. Vermeulen Characterizing spectrometry: opportunities.Trends Biotechnol. 34: 825-834Abstract done exogenous expression bait fused tag immunoprecipitation endogenous specific antibody. Antibodies immobilized resins magnetic agarose beads exposed lysates followed retrieval washing, prior elution digestion coimmunoprecipitated shotgun proteomics. Exogenous epitope FLAG HA advantage requiring antibody approach applied multiple tagged baits allow nonspecific overexpression false identifications levels itself Isotopic antibodies transfection alone negative controls. Initial decrease background focused dual scheme (416Gavin Bosche Krause Grandi Marzioch Bauer al.Functional organization proteome systematic analysis prot

Язык: Английский

---

Gut microenvironmental changes as a potential trigger in Parkinson’s disease through the gut–brain axis

Journal of Biomedical Science, Год журнала: 2022, Номер 29(1)

Опубликована: Июль 27, 2022

Abstract Parkinson’s disease (PD) is the second most common neurodegenerative attributed to synergistic effects of genetic risk and environmental stimuli. Although PD characterized by motor dysfunction resulting from intraneuronal alpha-synuclein accumulations, termed Lewy bodies, dopaminergic neuronal degeneration in substantia nigra, multiple systems are involved process, heterogenous clinical presentation progression. Genetic predisposition regarding aberrant immune responses, abnormal protein aggregation, autophagolysosomal impairment, mitochondrial leads vulnerable neurons that sensitive triggers and, together, result degeneration. Neuropathology studies have shown that, at least some patients, bodies start enteric nervous system then spread central through gut–brain axis, suggesting contribution an altered gut microenvironment pathogenesis PD. A plethora evidence has revealed different microbiomes metabolites patients with compared unaffected controls. Chronic inflammation impaired intestinal barrier integrity been observed human mouse models These observations led hypothesis a potential trigger process genetically susceptible host. In this review, we will discuss complex interplay between factors microenvironmental changes contributing pathogenesis.

Язык: Английский

---

Neurodegeneration and Neuroinflammation in Parkinson’s Disease: a Self-Sustained Loop

Current Neurology and Neuroscience Reports, Год журнала: 2022, Номер 22(8), С. 427 - 440

Опубликована: Июнь 8, 2022

Abstract Purpose of Review Neuroinflammation plays a significant role in Parkinson’s disease (PD) etiology along with mitochondrial dysfunction and impaired proteostasis. In this context, mechanisms related to immune response can act as modifiers at different steps the neurodegenerative process justify growing interest anti-inflammatory agents potential disease-modifying treatments PD. The discovery inherited gene mutations PD has allowed researchers develop cellular animal models study underlying biology, but original cause neuroinflammation is still debated date. Recent Findings Cell autonomous alterations neuronal cells, including damage protein aggregation, could play role, recent findings also highlighted importance intercellular communication both local systemic level. This given rise debate about non-neuronal cells reignited intense research into gut-brain axis other interactions development disease. Whatever trigger PD, what appears quite clear that aberrant activation glial components system creates vicious circle which neurodegeneration nourish each other. Summary review, we will provide an up-to-date summary main those induced by environmental factors (e.g. gut microbiome) genetic background affected patients. Starting from lesson provided familial forms discuss pathophysiological linked inflammation idiopathic forms. Finally, comment on clinical translatability immunobiomarkers identified patient cohorts update current therapeutic strategies aimed overcoming or preventing

Язык: Английский

---