Top

Published in:

Open Access 01-12-2015 | Review

Genotype-phenotype relationship in hereditary amyotrophic lateral sclerosis

Authors: Satoshi Yamashita, Yukio Ando

Published in: Translational Neurodegeneration | Issue 1/2015

Abstract

Amyotrophic lateral sclerosis (ALS) is the most common adult-onset motor neuron disease. It is characterized by neuronal loss and degeneration of the upper motor neurons (UMNs) and lower motor neurons (LMNs), and is usually fatal due to respiratory failure within 3–5 years of onset. Although approximately 5–10 % of patients with ALS have an inherited form of the disease, the distinction between hereditary and apparently sporadic ALS (SALS) seems to be artificial. Thus, genetic factors play a role in all types of ALS, to a greater or lesser extent. During the decade of upheaval, the evolution of molecular genetics technology has rapidly advanced our genetic knowledge about the causes of ALS, and the relationship between the genetic subtypes and clinical phenotype. In this review, we will focus on the possible genotype-phenotype correlation in hereditary ALS. Uncovering the identity of the genetic factors in ALS will not only improve the accuracy of ALS diagnosis, but may also provide new approaches for preventing and treating the disease.

Available only for authorised users

Siddique T, Figlewicz DA, Pericak-Vance MA, Haines JL, Rouleau G, Jeffers AJ, et al. Linkage of a gene causing familial amyotrophic lateral sclerosis to chromosome 21 and evidence of genetic-locus heterogeneity. N Engl J Med. 1991;324:1381–4. doi:10.1056/NEJM199105163242001.PubMedCrossRef

Rosen DR, Siddique T, Patterson D, Figlewicz DA, Sapp P, Hentati A, et al. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature. 1993;362:59–62. doi:10.1038/362059a0.PubMedCrossRef

Cudkowicz ME, McKenna-Yasek D, Sapp PE, Chin W, Geller B, Hayden DL, et al. Epidemiology of mutations in superoxide dismutase in amyotrophic lateral sclerosis. Ann Neurol. 1997;41:210–21. doi:10.1002/ana.410410212.PubMedCrossRef

Regal L, Vanopdenbosch L, Tilkin P, Van den Bosch L, Thijs V, Sciot R et al. The G93C mutation in superoxide dismutase 1: clinicopathologic phenotype and prognosis. Arch Neurol. 2006;63: 262-7. doi:10.1001/archneur.63.2.262

Aoki M, Warita H, Itoyama Y. Amyotrophic lateral sclerosis with the SOD1 mutations. Rinsho Shinkeigaku. 2008;48:966–9.PubMedCrossRef

Yamashita S, Kimura E, Yamamoto F, Migita A, Kanda E, Mita S et al. Flexor-dominant myopathic phenotype in patients with His46Arg substitution in the Cu/Zn superoxide dismutase gene. J Neurol Sci. 2009;281: 6-10. doi:10.1016/j.jns.2009.03.010

Crugnola V, Lamperti C, Lucchini V, Ronchi D, Peverelli L, Prelle A et al. Mitochondrial respiratory chain dysfunction in muscle from patients with amyotrophic lateral sclerosis. Arch Neurol. 2010;67: 849-54. doi:10.1001/archneurol.2010.128

Hadano S, Hand CK, Osuga H, Yanagisawa Y, Otomo A, Devon RS, et al. A gene encoding a putative GTPase regulator is mutated in familial amyotrophic lateral sclerosis 2. Nat Genet. 2001;29:166–73. doi:10.1038/ng1001-166.PubMedCrossRef

Yang Y, Hentati A, Deng HX, Dabbagh O, Sasaki T, Hirano M, et al. The gene encoding alsin, a protein with three guanine-nucleotide exchange factor domains, is mutated in a form of recessive amyotrophic lateral sclerosis. Nat Genet. 2001;29:160–5. doi:10.1038/ng1001-160.PubMedCrossRef

10.

Siddiqi S, Foo JN, Vu A, Azim S, Silver DL, Mansoor A, et al. A novel splice-site mutation in ALS2 establishes the diagnosis of juvenile amyotrophic lateral sclerosis in a family with early onset anarthria and generalized dystonias. PLoS One. 2014;9, e113258. doi:10.1371/journal.pone.0113258.PubMedCentralPubMedCrossRef

11.

Moreira MC, Klur S, Watanabe M, Nemeth AH, Le Ber I, Moniz JC, et al. Senataxin, the ortholog of a yeast RNA helicase, is mutant in ataxia-ocular apraxia 2. Nat Genet. 2004;36:225–7. doi:10.1038/ng1303.PubMedCrossRef

12.

Chen YZ, Bennett CL, Huynh HM, Blair IP, Puls I, Irobi J, et al. DNA/RNA helicase gene mutations in a form of juvenile amyotrophic lateral sclerosis (ALS4). Am J Hum Genet. 2004;74:1128–35. doi:10.1086/421054.PubMedCentralPubMedCrossRef

13.

De Jonghe P, Auer-Grumbach M, Irobi J, Wagner K, Plecko B, Kennerson M, et al. Autosomal dominant juvenile amyotrophic lateral sclerosis and distal hereditary motor neuronopathy with pyramidal tract signs: synonyms for the same disorder? Brain. 2002;125:1320–5.PubMedCrossRef

14.

Saracchi E, Castelli M, Bassi MT, Brighina E, Cereda D, Marzorati L, et al. A novel heterozygous SETX mutation in a patient presenting with chorea and motor neuron disease. Amyotroph Lateral Scler Frontotemporal Degener. 2014;15:138–40. doi:10.3109/21678421.2013.865751.PubMedCrossRef

15.

Arning L, Epplen JT, Rahikkala E, Hendrich C, Ludolph AC, Sperfeld AD. The SETX missense variation spectrum as evaluated in patients with ALS4-like motor neuron diseases. Neurogenetics. 2013;14:53–61. doi:10.1007/s10048-012-0347-4.PubMedCrossRef

16.

Stevanin G, Santorelli FM, Azzedine H, Coutinho P, Chomilier J, Denora PS et al. Mutations in SPG11, encoding spatacsin, are a major cause of spastic paraplegia with thin corpus callosum. Nat Genet. 2007;39: 366-72. doi:10.1038/ng1980

17.

Orlacchio A, Babalini C, Borreca A, Patrono C, Massa R, Basaran S et al. SPATACSIN mutations cause autosomal recessive juvenile amyotrophic lateral sclerosis. Brain. 2010;133: 591-8. doi:10.1093/brain/awp325

18.

Daoud H, Zhou S, Noreau A, Sabbagh M, Belzil V, Dionne-Laporte A et al. Exome sequencing reveals SPG11 mutations causing juvenile ALS. Neurobiol Aging. 2012;33: 839 e5-9. doi:10.1016/j.neurobiolaging.2011.11.012

19.

Kwiatkowski TJ, Jr., Bosco DA, Leclerc AL, Tamrazian E, Vanderburg CR, Russ C et al. Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science. 2009;323: 1205-8. doi:10.1126/science.1166066

20.

Vance C, Rogelj B, Hortobagyi T, De Vos KJ, Nishimura AL, Sreedharan J et al. Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science. 2009;323: 1208-11. doi:10.1126/science.1165942

21.

Suzuki N, Aoki M, Warita H, Kato M, Mizuno H, Shimakura N, et al. FALS with FUS mutation in Japan, with early onset, rapid progress and basophilic inclusion. J Hum Genet. 2010;55:252–4. doi:10.1038/jhg.2010.16.PubMedCrossRef

22.

Yamashita S, Mori A, Sakaguchi H, Suga T, Ishihara D, Ueda A, et al. Sporadic juvenile amyotrophic lateral sclerosis caused by mutant FUS/TLS: possible association of mental retardation with this mutation. J Neurol. 2012;259:1039–44. doi:10.1007/s00415-011-6292-6.PubMedCrossRef

23.

Munoz DG. FUS mutations in sporadic juvenile ALS: another step toward understanding ALS pathogenesis. Neurology. 2010;75: 584-5. doi:10.1212/WNL.0b013e3181ed9ee4

24.

Baumer D, Hilton D, Paine SM, Turner MR, Lowe J, Talbot K et al. Juvenile ALS with basophilic inclusions is a FUS proteinopathy with FUS mutations. Neurology. 2010;75: 611-8. doi:10.1212/WNL.0b013e3181ed9cde

25.

Conte A, Lattante S, Zollino M, Marangi G, Luigetti M, Del Grande A et al. P525L FUS mutation is consistently associated with a severe form of juvenile amyotrophic lateral sclerosis. Neuromuscul Disord. 2012;22: 73-5. doi:10.1016/j.nmd.2011.08.003

26.

Blair IP, Williams KL, Warraich ST, Durnall JC, Thoeng AD, Manavis J, et al. FUS mutations in amyotrophic lateral sclerosis: clinical, pathological, neurophysiological and genetic analysis. J Neurol Neurosurg Psychiatry. 2010;81:639–45. doi:10.1136/jnnp.2009.194399.PubMedCrossRef

27.

Yan J, Deng HX, Siddique N, Fecto F, Chen W, Yang Y et al. Frameshift and novel mutations in FUS in familial amyotrophic lateral sclerosis and ALS/dementia. Neurology. 2010;75: 807-14. doi:10.1212/WNL.0b013e3181f07e0c

28.

Dormann D, Madl T, Valori CF, Bentmann E, Tahirovic S, Abou-Ajram C et al. Arginine methylation next to the PY-NLS modulates Transportin binding and nuclear import of FUS. EMBO J. 2012;31: 4258-75. doi:10.1038/emboj.2012.261

29.

Dormann D, Rodde R, Edbauer D, Bentmann E, Fischer I, Hruscha A et al. ALS-associated fused in sarcoma (FUS) mutations disrupt Transportin-mediated nuclear import. EMBO J. 2010;29: 2841-57. doi:10.1038/emboj.2010.143

30.

Kino Y, Washizu C, Aquilanti E, Okuno M, Kurosawa M, Yamada M et al. Intracellular localization and splicing regulation of FUS/TLS are variably affected by amyotrophic lateral sclerosis-linked mutations. Nucleic Acids Res. 2011;39: 2781-98. doi:10.1093/nar/gkq1162

31.

Waibel S, Neumann M, Rabe M, Meyer T, Ludolph AC. Novel missense and truncating mutations in FUS/TLS in familial ALS. Neurology. 2010;75: 815-7. doi:10.1212/WNL.0b013e3181f07e26

32.

Nishimura AL, Mitne-Neto M, Silva HC, Richieri-Costa A, Middleton S, Cascio D, et al. A mutation in the vesicle-trafficking protein VAPB causes late-onset spinal muscular atrophy and amyotrophic lateral sclerosis. Am J Hum Genet. 2004;75:822–31. doi:10.1086/425287.PubMedCentralPubMedCrossRef

33.

Marques VD, Barreira AA, Davis MB, Abou-Sleiman PM, Silva Jr WA, Zago MA, et al. Expanding the phenotypes of the Pro56Ser VAPB mutation: proximal SMA with dysautonomia. Muscle Nerve. 2006;34:731–9. doi:10.1002/mus.20657.PubMedCrossRef

34.

Greenway MJ, Andersen PM, Russ C, Ennis S, Cashman S, Donaghy C et al. ANG mutations segregate with familial and 'sporadic' amyotrophic lateral sclerosis. Nat Genet. 2006;38: 411-3. doi:10.1038/ng1742

35.

van Es MA, Diekstra FP, Veldink JH, Baas F, Bourque PR, Schelhaas HJ et al. A case of ALS-FTD in a large FALS pedigree with a K17I ANG mutation. Neurology. 2009;72: 287-8. doi:10.1212/01.wnl.0000339487.84908.00

36.

van Es MA, Schelhaas HJ, van Vught PW, Ticozzi N, Andersen PM, Groen EJ, et al. Angiogenin variants in Parkinson disease and amyotrophic lateral sclerosis. Ann Neurol. 2011;70:964–73. doi:10.1002/ana.22611.PubMedCrossRef

37.

Sreedharan J, Blair IP, Tripathi VB, Hu X, Vance C, Rogelj B et al. TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science. 2008;319: 1668-72. doi:10.1126/science.1154584

38.

Kabashi E, Valdmanis PN, Dion P, Spiegelman D, McConkey BJ, Vande Velde C et al. TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis. Nat Genet. 2008;40: 572-4. doi:10.1038/ng.132

39.

Van Deerlin VM, Leverenz JB, Bekris LM, Bird TD, Yuan W, Elman LB et al. TARDBP mutations in amyotrophic lateral sclerosis with TDP-43 neuropathology: a genetic and histopathological analysis. Lancet Neurol. 2008;7: 409-16. doi:10.1016/S1474-4422(08)70071-1

40.

Yokoseki A, Shiga A, Tan CF, Tagawa A, Kaneko H, Koyama A, et al. TDP-43 mutation in familial amyotrophic lateral sclerosis. Ann Neurol. 2008;63:538–42. doi:10.1002/ana.21392.PubMedCrossRef

41.

Corcia P, Valdmanis P, Millecamps S, Lionnet C, Blasco H, Mouzat K et al. Phenotype and genotype analysis in amyotrophic lateral sclerosis with TARDBP gene mutations. Neurology. 2012;78: 1519-26. doi:10.1212/WNL.0b013e3182553c88

42.

Chow CY, Zhang Y, Dowling JJ, Jin N, Adamska M, Shiga K et al. Mutation of FIG4 causes neurodegeneration in the pale tremor mouse and patients with CMT4J. Nature. 2007;448: 68-72. doi:10.1038/nature05876

43.

Chow CY, Landers JE, Bergren SK, Sapp PC, Grant AE, Jones JM et al. Deleterious variants of FIG4, a phosphoinositide phosphatase, in patients with ALS. Am J Hum Genet. 2009;84: 85-8. doi:10.1016/j.ajhg.2008.12.010

44.

Maruyama H, Morino H, Ito H, Izumi Y, Kato H, Watanabe Y et al. Mutations of optineurin in amyotrophic lateral sclerosis. Nature. 2010;465: 223-6. doi:10.1038/nature08971

45.

Cirulli ET, Lasseigne BN, Petrovski S, Sapp PC, Dion PA, Leblond CS, et al. Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways. Science. 2015;347:1436–41. doi:10.1126/science.aaa3650.PubMedCrossRef

46.

Freischmidt A, Wieland T, Richter B, Ruf W, Schaeffer V, Muller K, et al. Haploinsufficiency of TBK1 causes familial ALS and fronto-temporal dementia. Nat Neurosci. 2015;18:631–6. doi:10.1038/nn.4000.PubMedCrossRef

47.

Pulst SM, Nechiporuk A, Nechiporuk T, Gispert S, Chen XN, Lopes-Cendes I, et al. Moderate expansion of a normally biallelic trinucleotide repeat in spinocerebellar ataxia type 2. Nat Genet. 1996;14:269–76. doi:10.1038/ng1196-269.PubMedCrossRef

48.

Elden AC, Kim HJ, Hart MP, Chen-Plotkin AS, Johnson BS, Fang X et al. Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS. Nature. 2010;466: 1069-75. doi:10.1038/nature09320

49.

Chen Y, Huang R, Yang Y, Chen K, Song W, Pan P et al. Ataxin-2 intermediate-length polyglutamine: a possible risk factor for Chinese patients with amyotrophic lateral sclerosis. Neurobiol Aging. 2011;32: 1925 e1-5. doi:10.1016/j.neurobiolaging.2011.05.015

50.

Liu X, Lu M, Tang L, Zhang N, Chui D, Fan D. ATXN2 CAG repeat expansions increase the risk for Chinese patients with amyotrophic lateral sclerosis. Neurobiol Aging. 2013;34: 2236 e5-8. doi:10.1016/j.neurobiolaging.2013.04.009

51.

Van Damme P, Veldink JH, van Blitterswijk M, Corveleyn A, van Vught PW, Thijs V et al. Expanded ATXN2 CAG repeat size in ALS identifies genetic overlap between ALS and SCA2. Neurology. 2011;76: 2066-72. doi:10.1212/WNL.0b013e31821f445b

52.

Johnson JO, Mandrioli J, Benatar M, Abramzon Y, Van Deerlin VM, Trojanowski JQ et al. Exome sequencing reveals VCP mutations as a cause of familial ALS. Neuron. 2010;68: 857-64. doi:10.1016/j.neuron.2010.11.036

53.

Watts GD, Wymer J, Kovach MJ, Mehta SG, Mumm S, Darvish D, et al. Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein. Nat Genet. 2004;36:377–81. doi:10.1038/ng1332.PubMedCrossRef

54.

Gonzalez-Perez P, Cirulli ET, Drory VE, Dabby R, Nisipeanu P, Carasso RL et al. Novel mutation in VCP gene causes atypical amyotrophic lateral sclerosis. Neurology. 2012;79: 2201-8. doi:10.1212/WNL.0b013e318275963b

55.

Deng HX, Chen W, Hong ST, Boycott KM, Gorrie GH, Siddique N et al. Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia. Nature. 2011;477: 211-5. doi:10.1038/nature10353

56.

Al-Saif A, Al-Mohanna F, Bohlega S. A mutation in sigma-1 receptor causes juvenile amyotrophic lateral sclerosis. Ann Neurol. 2011;70:913–9. doi:10.1002/ana.22534.PubMedCrossRef

57.

Fecto F, Siddique T. SIGMAR1 mutations, genetic heterogeneity at the chromosome 9p locus, and the expanding etiological diversity of amyotrophic lateral sclerosis. Ann Neurol. 2011;70:867–70. doi:10.1002/ana.22648.PubMedCrossRef

58.

Belzil VV, Daoud H, Camu W, Strong MJ, Dion PA, Rouleau GA. Genetic analysis of SIGMAR1 as a cause of familial ALS with dementia. Eur J Hum Genet. 2013;21: 237-9. doi:10.1038/ejhg.2012.135

59.

Skibinski G, Parkinson NJ, Brown JM, Chakrabarti L, Lloyd SL, Hummerich H, et al. Mutations in the endosomal ESCRTIII-complex subunit CHMP2B in frontotemporal dementia. Nat Genet. 2005;37:806–8. doi:10.1038/ng1609.PubMedCrossRef

60.

Parkinson N, Ince PG, Smith MO, Highley R, Skibinski G, Andersen PM et al. ALS phenotypes with mutations in CHMP2B (charged multivesicular body protein 2B). Neurology. 2006;67: 1074-7. doi:10.1212/01.wnl.0000231510.89311.8b

61.

Cox LE, Ferraiuolo L, Goodall EF, Heath PR, Higginbottom A, Mortiboys H, et al. Mutations in CHMP2B in lower motor neuron predominant amyotrophic lateral sclerosis (ALS). PLoS One. 2010;5, e9872. doi:10.1371/journal.pone.0009872.PubMedCentralPubMedCrossRef

62.

Wu CH, Fallini C, Ticozzi N, Keagle PJ, Sapp PC, Piotrowska K et al. Mutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis. Nature. 2012;488: 499-503. doi:10.1038/nature11280

63.

Takahashi Y, Fukuda Y, Yoshimura J, Toyoda A, Kurppa K, Moritoyo H, et al. ERBB4 mutations that disrupt the neuregulin-ErbB4 pathway cause amyotrophic lateral sclerosis type 19. Am J Hum Genet. 2013;93:900–5. doi:10.1016/j.ajhg.2013.09.008.PubMedCentralPubMedCrossRef

64.

Kim HJ, Kim NC, Wang YD, Scarborough EA, Moore J, Diaz Z, et al. Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS. Nature. 2013;495:467–73. doi:10.1038/nature11922.PubMedCentralPubMedCrossRef

65.

Johnson JO, Pioro EP, Boehringer A, Chia R, Feit H, Renton AE, et al. Mutations in the Matrin 3 gene cause familial amyotrophic lateral sclerosis. Nat Neurosci. 2014;17:664–6. doi:10.1038/nn.3688.PubMedCentralPubMedCrossRef

66.

Senderek J, Garvey SM, Krieger M, Guergueltcheva V, Urtizberea A, Roos A, et al. Autosomal-dominant distal myopathy associated with a recurrent missense mutation in the gene encoding the nuclear matrix protein, matrin 3. Am J Hum Genet. 2009;84:511–8. doi:10.1016/j.ajhg.2009.03.006.PubMedCentralPubMedCrossRef

67.

Yamashita S, Mori A, Nishida Y, Kurisaki R, Tawara N, Nishikami T, et al. Clinicopathological features of the first Asian family having vocal cord and pharyngeal weakness with distal myopathy due to a MATR3 mutation. Neuropathol Appl Neurobiol. 2015;41:391–8. doi:10.1111/nan.12179.PubMedCrossRef

68.

DeJesus-Hernandez M, Mackenzie IR, Boeve BF, Boxer AL, Baker M, Rutherford NJ et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron. 2011;72: 245-56. doi:10.1016/j.neuron.2011.09.011

69.

Renton AE, Majounie E, Waite A, Simon-Sanchez J, Rollinson S, Gibbs JR et al. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron. 2011;72: 257-68. doi:10.1016/j.neuron.2011.09.010

70.

Majounie E, Renton AE, Mok K, Dopper EG, Waite A, Rollinson S et al. Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study. Lancet Neurol. 2012;11: 323-30. doi:10.1016/S1474-4422(12)70043-1.

71.

Rutherford NJ, Heckman MG, Dejesus-Hernandez M, Baker MC, Soto-Ortolaza AI, Rayaprolu S et al. Length of normal alleles of C9ORF72 GGGGCC repeat do not influence disease phenotype. Neurobiol Aging. 2012;33: 2950 e5-7. doi:10.1016/j.neurobiolaging.2012.07.005

72.

Bannwarth S, Ait-El-Mkadem S, Chaussenot A, Genin EC, Lacas-Gervais S, Fragaki K, et al. A mitochondrial origin for frontotemporal dementia and amyotrophic lateral sclerosis through CHCHD10 involvement. Brain. 2014;137:2329–45. doi:10.1093/brain/awu138.PubMedCrossRef

73.

Pottier C, Bieniek KF, Finch N, van de Vorst M, Baker M, Perkersen R, et al. Whole-genome sequencing reveals important role for TBK1 and OPTN mutations in frontotemporal lobar degeneration without motor neuron disease. Acta Neuropathol. 2015. doi:10.1007/s00401-015-1436-x.PubMed

74.

Fanos JH, Gelinas DF, Miller RG. "You have shown me my end": attitudes toward presymptomatic testing for familial amyotrophic lateral sclerosis. Am J Med Genet A. 2004;129A:248–53. doi:10.1002/ajmg.a.30178.PubMedCrossRef

Title: Genotype-phenotype relationship in hereditary amyotrophic lateral sclerosis
Authors: Satoshi Yamashita
Yukio Ando
Publication date: 01-12-2015
Publisher: BioMed Central
Published in: Translational Neurodegeneration / Issue 1/2015
Electronic ISSN: 2047-9158
DOI: https://doi.org/10.1186/s40035-015-0036-y

At a glance: The STEP trials

Springer Medicine

Genotype-phenotype relationship in hereditary amyotrophic lateral sclerosis

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 1/2015

Development of stem cell-based therapy for Parkinson’s disease

How to optimize the treatment of early stage Parkinson’s disease

New developments and future opportunities in biomarkers for amyotrophic lateral sclerosis

Meta-analyses on prevalence of selected Parkinson’s nonmotor symptoms before and after diagnosis

Treatment of the later stages of Parkinson’s disease – pharmacological approaches now and in the future

The endosomal-lysosomal system: from acidification and cargo sorting to neurodegeneration