Top

13-03-2024 | Parkinson's Disease | Neurology and Preclinical Neurological Studies - Original Article

Pathogenesis of Parkinson’s disease: from hints from monogenic familial PD to biomarkers

Authors: Nobutaka Hattori, Manabu Funayama, Yuzuru Imai, Taku Hatano

Published in: Journal of Neural Transmission

Abstract

Twenty-five years have passed since the causative gene for familial Parkinson's disease (PD), Parkin (now PRKN), was identified in 1998; PRKN is the most common causative gene in young-onset PD. Parkin encodes a ubiquitin-protein ligase, and Parkin is involved in mitophagy, a type of macroautophagy, in concert with PTEN-induced kinase 1 (PINK1). Both gene products are also involved in mitochondrial quality control. Among the many genetic PD-causing genes discovered, discovering PRKN as a cause of juvenile-onset PD has significantly impacted other neurodegenerative disorders. This is because the involvement of proteolytic systems has been suggested as a common mechanism in neurodegenerative diseases in which inclusion body formation is observed. The discovery of the participation of PRKN in PD has brought attention to the involvement of the proteolytic system in neurodegenerative diseases. Our research group has successfully isolated and identified CHCHD2, which is involved in the mitochondrial electron transfer system, and prosaposin (PSAP), which is involved in the lysosomal system, in this Parkin mechanism. Hereditary PD is undoubtedly an essential clue to solitary PD, and at least 25 or so genes and loci have been reported so far. This number of genes indicates that PD is a very diverse group of diseases. Currently, the diagnosis of PD is based on clinical symptoms and imaging studies. Although highly accurate diagnostic criteria have been published, early diagnosis is becoming increasingly important in treatment strategies for neurodegenerative diseases. Here, we also describe biomarkers that our group is working on.

Aflaki E, Westbroek W, Sidransky E (2017) The complicated relationship between Gaucher disease and parkinsonism: insights from a rare disease. Neuron 93(4):737–746. https://doi.org/10.1016/j.neuron.2017.01.018CrossRefPubMedPubMedCentral

Asakawa S, Abe I, Kudoh Y, Kishi N, Wang Y, Kubota R, Kudoh J, Kawasaki K, Minoshima S, Shimizu N (1997) Human BAC library: construction and rapid screening. Gene 191(1):69–79. https://doi.org/10.1016/s0378-1119(97)00044-9CrossRefPubMed

Bannwarth S, Ait-El-Mkadem S, Chaussenot A, Genin EC, Lacas-Gervais S, Fragaki K, Berg-Alonso L, Kageyama Y, Serre V, Moore DG, Verschueren A, Rouzier C, Le Ber I, Auge G, Cochaud C, Lespinasse F, N’Guyen K, de Septenville A, Brice A, Yu-Wai-Man P, Sesaki H, Pouget J, Paquis-Flucklinger V (2014) A mitochondrial origin for frontotemporal dementia and amyotrophic lateral sclerosis through CHCHD10 involvement. Brain 137(Pt 8):2329–2345. https://doi.org/10.1093/brain/awu138CrossRefPubMedPubMedCentral

Barodia SK, McMeekin LJ, Creed RB, Quinones EK, Cowell RM, Goldberg MS (2019) PINK1 phosphorylates ubiquitin predominantly in astrocytes. NPJ Parkinsons Dis 5:29. https://doi.org/10.1038/s41531-019-0101-9CrossRefPubMedPubMedCentral

Cardoso F, Goetz CG, Mestre TA, Sampaio C, Adler CH, Berg D, Bloem BR, Burn DJ, Fitts MS, Gasser T, Klein C, de Tijssen MAJ, Lang AE, Lim SY, Litvan I, Meissner WG, Mollenhauer B, Okubadejo N, Okun MS, Postuma RB, Svenningsson P, Tan LCS, Tsunemi T, Wahlstrom-Helgren S, Gershanik OS, Fung VSC, Trenkwalder C (2023) A statement of the MDS on biological definition, staging, and classification of Parkinson’s disease. Mov Disord. https://doi.org/10.1002/mds.29683CrossRefPubMed

Castelo Rueda MP, Zanon A, Gilmozzi V, Lavdas AA, Raftopoulou A, Delcambre S, Del Greco MF, Klein C, Grunewald A, Pramstaller PP, Hicks AA, Pichler I (2023) Molecular phenotypes of mitochondrial dysfunction in clinically non-manifesting heterozygous PRKN variant carriers. NPJ Parkinsons Dis 9(1):65. https://doi.org/10.1038/s41531-023-00499-9CrossRefPubMedPubMedCentral

Cossu D, Yokoyama K, Sato S, Noda S, Sechi LA, Hattori N (2021) PARKIN modifies peripheral immune response and increases neuroinflammation in active experimental autoimmune encephalomyelitis (EAE). J Neuroimmunol 359:577694. https://doi.org/10.1016/j.jneuroim.2021.577694CrossRefPubMed

Daida K, Funayama M, Billingsley KJ, Malik L, Miano-Burkhardt A, Leonard HL, Makarious MB, Iwaki H, Ding J, Gibbs JR, Ishiguro M, Yoshino H, Ogaki K, Oyama G, Nishioka K, Nonaka R, Akamatsu W, Blauwendraat C, Hattori N (2023) Long-read sequencing resolves a complex structural variant in PRKN Parkinson’s disease. Mov Disord 38(12):2249–2257. https://doi.org/10.1002/mds.29610CrossRefPubMed

Funayama M, Ohe K, Amo T, Furuya N, Yamaguchi J, Saiki S, Li Y, Ogaki K, Ando M, Yoshino H, Tomiyama H, Nishioka K, Hasegawa K, Saiki H, Satake W, Mogushi K, Sasaki R, Kokubo Y, Kuzuhara S, Toda T, Mizuno Y, Uchiyama Y, Ohno K, Hattori N (2015) CHCHD2 mutations in autosomal dominant late-onset Parkinson’s disease: a genome-wide linkage and sequencing study. Lancet Neurol 14(3):274–282. https://doi.org/10.1016/S1474-4422(14)70266-2CrossRefPubMed

Hattori N, Kitada T, Matsumine H, Asakawa S, Yamamura Y, Yoshino H, Kobayashi T, Yokochi M, Wang M, Yoritaka A, Kondo T, Kuzuhara S, Nakamura S, Shimizu N, Mizuno Y (1998) Molecular genetic analysis of a novel Parkin gene in Japanese families with autosomal recessive juvenile parkinsonism: evidence for variable homozygous deletions in the Parkin gene in affected individuals. Ann Neurol 44(6):935–941. https://doi.org/10.1002/ana.410440612CrossRefPubMed

He Y, Kaya I, Shariatgorji R, Lundkvist J, Wahlberg LU, Nilsson A, Mamula D, Kehr J, Zareba-Paslawska J, Biverstal H, Chergui K, Zhang X, Andren PE, Svenningsson P (2023) Prosaposin maintains lipid homeostasis in dopamine neurons and counteracts experimental parkinsonism in rodents. Nat Commun 14(1):5804. https://doi.org/10.1038/s41467-023-41539-5ADSCrossRefPubMedPubMedCentral

Hedrich K, Marder K, Harris J, Kann M, Lynch T, Meija-Santana H, Pramstaller PP, Schwinger E, Bressman SB, Fahn S, Klein C (2002) Evaluation of 50 probands with early-onset Parkinson’s disease for Parkin mutations. Neurology 58(8):1239–1246. https://doi.org/10.1212/wnl.58.8.1239CrossRefPubMed

Hristova VA, Beasley SA, Rylett RJ, Shaw GS (2009) Identification of a novel Zn2+-binding domain in the autosomal recessive juvenile Parkinson-related E3 ligase parkin. J Biol Chem 284(22):14978–14986. https://doi.org/10.1074/jbc.M808700200CrossRefPubMedPubMedCentral

Ikeda A, Matsushima T, Daida K, Nakajima S, Conedera S, Li Y, Yoshino H, Oyama G, Funayama M, Nishioka K, Hattori N (2017) A novel mutation of CHCHD2 p. R8H in a sporadic case of Parkinson’s disease. Parkinsonism Relat Disord 34:66–68. https://doi.org/10.1016/j.parkreldis.2016.10.018CrossRefPubMed

Ikeda A, Nishioka K, Meng H, Takanashi M, Hasegawa I, Inoshita T, Shiba-Fukushima K, Li Y, Yoshino H, Mori A, Okuzumi A, Yamaguchi A, Nonaka R, Izawa N, Ishikawa KI, Saiki H, Morita M, Hasegawa M, Hasegawa K, Elahi M, Funayama M, Okano H, Akamatsu W, Imai Y, Hattori N (2019) Mutations in CHCHD2 cause alpha-synuclein aggregation. Hum Mol Genet 28(23):3895–3911. https://doi.org/10.1093/hmg/ddz241CrossRefPubMed

Ikeda A, Imai Y, Hattori N (2022) Neurodegeneration-associated mitochondrial proteins, CHCHD2 and CHCHD10-what distinguishes the two? Front Cell Dev Biol 10:996061. https://doi.org/10.3389/fcell.2022.996061CrossRefPubMedPubMedCentral

Kano M, Takanashi M, Oyama G, Yoritaka A, Hatano T, Shiba-Fukushima K, Nagai M, Nishiyama K, Hasegawa K, Inoshita T, Ishikawa KI, Akamatsu W, Imai Y, Bolognin S, Schwamborn JC, Hattori N (2020) Reduced astrocytic reactivity in human brains and midbrain organoids with PRKN mutations. NPJ Parkinsons Dis 6(1):33. https://doi.org/10.1038/s41531-020-00137-8CrossRefPubMedPubMedCentral

Khan NL, Graham E, Critchley P, Schrag AE, Wood NW, Lees AJ, Bhatia KP, Quinn N (2003) Parkin disease: a phenotypic study of a large case series. Brain 126(Pt 6):1279–1292. https://doi.org/10.1093/brain/awg142CrossRefPubMed

Kitada T, Asakawa S, Hattori N, Matsumine H, Yamamura Y, Minoshima S, Yokochi M, Mizuno Y, Shimizu N (1998) Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 392(6676):605–608. https://doi.org/10.1038/33416ADSCrossRefPubMed

Matsuda N, Sato S, Shiba K, Okatsu K, Saisho K, Gautier CA, Sou YS, Saiki S, Kawajiri S, Sato F, Kimura M, Komatsu M, Hattori N, Tanaka K (2010) PINK1 stabilized by mitochondrial depolarization recruits Parkin to damaged mitochondria and activates latent Parkin for mitophagy. J Cell Biol 189(2):211–221. https://doi.org/10.1083/jcb.200910140CrossRefPubMedPubMedCentral

Matsumine H, Saito M, Shimoda-Matsubayashi S, Tanaka H, Ishikawa A, Nakagawa-Hattori Y, Yokochi M, Kobayashi T, Igarashi S, Takano H, Sanpei K, Koike R, Mori H, Kondo T, Mizutani Y, Schaffer AA, Yamamura Y, Nakamura S, Kuzuhara S, Tsuji S, Mizuno Y (1997) Localization of a gene for an autosomal recessive form of juvenile Parkinsonism to chromosome 6q25.2–27. Am J Hum Genet 60(3):588–596PubMedPubMedCentral

Matsumine H, Yamamura Y, Hattori N, Kobayashi T, Kitada T, Yoritaka A, Mizuno Y (1998) A microdeletion of D6S305 in a family of autosomal recessive juvenile parkinsonism (PARK2). Genomics 49(1):143–146. https://doi.org/10.1006/geno.1997.5196CrossRefPubMed

Meng H, Yamashita C, Shiba-Fukushima K, Inoshita T, Funayama M, Sato S, Hatta T, Natsume T, Umitsu M, Takagi J, Imai Y, Hattori N (2017) Loss of Parkinson’s disease-associated protein CHCHD2 affects mitochondrial crista structure and destabilizes cytochrome c. Nat Commun 8:15500. https://doi.org/10.1038/ncomms15500ADSCrossRefPubMedPubMedCentral

Mitsui J, Takahashi Y, Goto J, Tomiyama H, Ishikawa S, Yoshino H, Minami N, Smith DI, Lesage S, Aburatani H, Nishino I, Brice A, Hattori N, Tsuji S (2010) Mechanisms of genomic instabilities underlying two common fragile-site-associated loci, PARK2 and DMD, in germ cell and cancer cell lines. Am J Hum Genet 87(1):75–89. https://doi.org/10.1016/j.ajhg.2010.06.006CrossRefPubMedPubMedCentral

Mori H, Kondo T, Yokochi M, Matsumine H, Nakagawa-Hattori Y, Miyake T, Suda K, Mizuno Y (1998) Pathologic and biochemical studies of juvenile parkinsonism linked to chromosome 6q. Neurology 51(3):890–892. https://doi.org/10.1212/wnl.51.3.890CrossRefPubMed

Narendra D, Tanaka A, Suen DF, Youle RJ (2008) Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. J Cell Biol 183(5):795–803. https://doi.org/10.1083/jcb.200809125CrossRefPubMedPubMedCentral

Narendra DP, Jin SM, Tanaka A, Suen DF, Gautier CA, Shen J, Cookson MR, Youle RJ (2010) PINK1 is selectively stabilized on impaired mitochondria to activate Parkin. PLoS Biol 8(1):e1000298. https://doi.org/10.1371/journal.pbio.1000298CrossRefPubMedPubMedCentral

Nicoletti G, Gagliardi M, Procopio R, Iannello G, Morelli M, Annesi G, Quattrone A (2018) A new CHCHD2 mutation identified in a southern Italy patient with multiple system atrophy. Parkinsonism Relat Disord 47:91–93. https://doi.org/10.1016/j.parkreldis.2017.12.005CrossRefPubMed

Ogaki K, Koga S, Heckman MG, Fiesel FC, Ando M, Labbe C, Lorenzo-Betancor O, Moussaud-Lamodiere EL, Soto-Ortolaza AI, Walton RL, Strongosky AJ, Uitti RJ, McCarthy A, Lynch T, Siuda J, Opala G, Rudzinska M, Krygowska-Wajs A, Barcikowska M, Czyzewski K, Puschmann A, Nishioka K, Funayama M, Hattori N, Parisi JE, Petersen RC, Graff-Radford NR, Boeve BF, Springer W, Wszolek ZK, Dickson DW, Ross OA (2015) Mitochondrial targeting sequence variants of the CHCHD2 gene are a risk for Lewy body disorders. Neurology 85(23):2016–2025. https://doi.org/10.1212/WNL.0000000000002170CrossRefPubMedPubMedCentral

Oji Y, Hatano T, Ueno SI, Funayama M, Ishikawa KI, Okuzumi A, Noda S, Sato S, Satake W, Toda T, Li Y, Hino-Takai T, Kakuta S, Tsunemi T, Yoshino H, Nishioka K, Hattori T, Mizutani Y, Mutoh T, Yokochi F, Ichinose Y, Koh K, Shindo K, Takiyama Y, Hamaguchi T, Yamada M, Farrer MJ, Uchiyama Y, Akamatsu W, Wu YR, Matsuda J, Hattori N (2020) Variants in saposin D domain of prosaposin gene linked to Parkinson’s disease. Brain 143(4):1190–1205. https://doi.org/10.1093/brain/awaa064CrossRefPubMed

Okuzumi A, Hatano T, Matsumoto G, Nojiri S, Ueno SI, Imamichi-Tatano Y, Kimura H, Kakuta S, Kondo A, Fukuhara T, Li Y, Funayama M, Saiki S, Taniguchi D, Tsunemi T, McIntyre D, Gerardy JJ, Mittelbronn M, Kruger R, Uchiyama Y, Nukina N, Hattori N (2023) Propagative alpha-synuclein seeds as serum biomarkers for synucleinopathies. Nat Med 29(6):1448–1455. https://doi.org/10.1038/s41591-023-02358-9CrossRefPubMedPubMedCentral

Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A, Pike B, Root H, Rubenstein J, Boyer R, Stenroos ES, Chandrasekharappa S, Athanassiadou A, Papapetropoulos T, Johnson WG, Lazzarini AM, Duvoisin RC, Di Iorio G, Golbe LI, Nussbaum RL (1997) Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science 276(5321):2045–2047. https://doi.org/10.1126/science.276.5321.2045CrossRefPubMed

Schrag A, Schott JM (2006) Epidemiological, clinical, and genetic characteristics of early-onset Parkinsonism. Lancet Neurol 5(4):355–363. https://doi.org/10.1016/S1474-4422(06)70411-2CrossRefPubMed

Shiba-Fukushima K, Imai Y, Yoshida S, Ishihama Y, Kanao T, Sato S, Hattori N (2012) PINK1-mediated phosphorylation of the Parkin ubiquitin-like domain primes mitochondrial translocation of Parkin and regulates mitophagy. Sci Rep 2:1002. https://doi.org/10.1038/srep01002ADSCrossRefPubMedPubMedCentral

Shiba-Fukushima K, Arano T, Matsumoto G, Inoshita T, Yoshida S, Ishihama Y, Ryu KY, Nukina N, Hattori N, Imai Y (2014) Phosphorylation of mitochondrial polyubiquitin by PINK1 promotes Parkin mitochondrial tethering. PLoS Genet 10(12):e1004861. https://doi.org/10.1371/journal.pgen.1004861CrossRefPubMedPubMedCentral

Shimoda-Matsubayashi S, Hattori T, Matsumine H, Shinohara A, Yoritaka A, Mori H, Kondo T, Chiba M, Mizuno Y (1997) Mn SOD activity and protein in a patient with chromosome 6-linked autosomal recessive parkinsonism in comparison with Parkinson’s disease and control. Neurology 49(5):1257–1262. https://doi.org/10.1212/wnl.49.5.1257CrossRefPubMed

Shimura H, Hattori N, Kubo S, Mizuno Y, Asakawa S, Minoshima S, Shimizu N, Iwai K, Chiba T, Tanaka K, Suzuki T (2000) Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase. Nat Genet 25(3):302–305. https://doi.org/10.1038/77060CrossRefPubMed

Siderowf A, Concha-Marambio L, Lafontant DE, Farris CM, Ma Y, Urenia PA, Nguyen H, Alcalay RN, Chahine LM, Foroud T, Galasko D, Kieburtz K, Merchant K, Mollenhauer B, Poston KL, Seibyl J, Simuni T, Tanner CM, Weintraub D, Videnovic A, Choi SH, Kurth R, Caspell-Garcia C, Coffey CS, Frasier M, Oliveira LMA, Hutten SJ, Sherer T, Marek K, Soto C, Parkinson’s Progression Markers I (2023) Assessment of heterogeneity among participants in the Parkinson’s Progression Markers Initiative cohort using alpha-synuclein seed amplification: a cross-sectional study. Lancet Neurol 22(5):407–417. https://doi.org/10.1016/S1474-4422(23)00109-6CrossRefPubMedPubMedCentral

Sidransky E, Nalls MA, Aasly JO, Aharon-Peretz J, Annesi G, Barbosa ER, Bar-Shira A, Berg D, Bras J, Brice A, Chen CM, Clark LN, Condroyer C, De Marco EV, Durr A, Eblan MJ, Fahn S, Farrer MJ, Fung HC, Gan-Or Z, Gasser T, Gershoni-Baruch R, Giladi N, Griffith A, Gurevich T, Januario C, Kropp P, Lang AE, Lee-Chen GJ, Lesage S, Marder K, Mata IF, Mirelman A, Mitsui J, Mizuta I, Nicoletti G, Oliveira C, Ottman R, Orr-Urtreger A, Pereira LV, Quattrone A, Rogaeva E, Rolfs A, Rosenbaum H, Rozenberg R, Samii A, Samaddar T, Schulte C, Sharma M, Singleton A, Spitz M, Tan EK, Tayebi N, Toda T, Troiano AR, Tsuji S, Wittstock M, Wolfsberg TG, Wu YR, Zabetian CP, Zhao Y, Ziegler SG (2009) Multicenter analysis of glucocerebrosidase mutations in Parkinson’s disease. N Engl J Med 361(17):1651–1661. https://doi.org/10.1056/NEJMoa0901281CrossRefPubMedPubMedCentral

Takahashi H, Ohama E, Suzuki S, Horikawa Y, Ishikawa A, Morita T, Tsuji S, Ikuta F (1994) Familial juvenile parkinsonism: clinical and pathologic study in a family. Neurology 44(3 Pt 1):437–441. https://doi.org/10.1212/wnl.44.3_part_1.437CrossRefPubMed

Yamamura Y, Sobue I, Ando K, Iida M, Yanagi T (1973) Paralysis agitans of early onset with marked diurnal fluctuation of symptoms. Neurology 23(3):239–244CrossRefPubMed

Yamamura Y, Kuzuhara S, Kondo K, Yanagi T, Uchida M, Matsumine H, Mizuno Y (1998) Clinical, pathologic and genetic studies on autosomal recessive early-onset Parkinsonism with diurnal fluctuation. Parkinsonism Relat Disord 4(2):65–72. https://doi.org/10.1016/s1353-8020(98)00015-7CrossRefPubMed

Yang X, Zhao Q, An R, Zheng J, Tian S, Chen Y, Xu Y (2016) Mutational scanning of the CHCHD2 gene in Han Chinese patients with Parkinson’s disease and meta-analysis of the literature. Parkinsonism Relat Disord 29:42–46. https://doi.org/10.1016/j.parkreldis.2016.05.032CrossRefPubMed

Yoshino H, Li Y, Nishioka K, Daida K, Hayashida A, Ishiguro Y, Yamada D, Izawa N, Nishi K, Nishikawa N, Oyama G, Hatano T, Nakamura S, Yoritaka A, Motoi Y, Funayama M, Hattori N, investigators of Japan Parkinson disease genetic s (2022) Genotype-phenotype correlation of Parkinson’s disease with PRKN variants. Neurobiol Aging 114:117–128. https://doi.org/10.1016/j.neurobiolaging.2021.12.014CrossRefPubMed

Zaltieri M, Longhena F, Pizzi M, Missale C, Spano P, Bellucci A (2015) Mitochondrial dysfunction and alpha-synuclein synaptic pathology in Parkinson’s disease: who’s on first? Parkinsons Dis 2015:108029. https://doi.org/10.1155/2015/108029CrossRefPubMedPubMedCentral

Title: Pathogenesis of Parkinson’s disease: from hints from monogenic familial PD to biomarkers
Authors: Nobutaka Hattori
Manabu Funayama
Yuzuru Imai
Taku Hatano
Publication date: 13-03-2024
Publisher: Springer Vienna
Keywords: Parkinson's Disease
Biomarkers
Published in: Journal of Neural Transmission
Print ISSN: 0300-9564
Electronic ISSN: 1435-1463
DOI: https://doi.org/10.1007/s00702-024-02747-5

At a glance: The STEP trials

Springer Medicine

Pathogenesis of Parkinson’s disease: from hints from monogenic familial PD to biomarkers

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

Please log in to get access to this content