Genetics and Epigenetics of Neurodegeneration

Our group focuses on the genetics, epigenetics and molecular mechanisms of amyotrophic lateral sclerosis (ALS) characterized by the progressive loss of motoneurons in motor cortex, brainstem and spinal cord. ALS is a highly heterogenous disease with multiple genetic and/or environmental causes.

In genetics, we use whole-exome-sequencing of ALS patients with a family history of the disease to identify novel genes and variants associated with the disease. Furthermore, we are interested in downstream effects of such genetic mutations and also in functional consequences of epigenetic alterations to better understand ALS pathogenesis. Recently, we started to focus on converging mechanisms that contribute to the disease independently of the underlying cause. Here, we aim to identify novel pathways and therapeutic targets that may provide a basis for the development of treatment options effective in all ALS patients.

In our work, we use various state-of-the-art techniques to decipher pathogenic mechanisms at the cellular and molecular level, and actively participate in several national and international collaborations. The generous contribution of ALS patients visiting the ALS outpatient clinic Ulm furthermore enables us to validate our in vitro findings in patient derived biomaterial.

Mitarbeiter der AG Molecular Genetic and Epigenetic of Neurodegeneration
Profilbild von Dr. rer. nat Axel Freischmidt

Dr. rer. nat Axel Freischmidt

Sarah Müller, M.Sc.

PhD student

Tel: +49 731-500 63051
Fax: +49 731-500 63050
Email: sarah-1.mueller@uni-​


Sonja Menge, M.Sc.

PhD student

Tel: +49 731-500 63051
Fax: +49 731-500 63050
Email: sonja.menge@uni-​


Lorena Decker, M.Sc.

PhD student

Tel: +49 731-500 63051
Fax: +49 731-500 63050
Email: lorena.decker@uni-​


Maike Haas

MD candidate

Tel: +49 731-500 63060
Fax: +49 731-500 63050



Nadine Todt
Medizinisch-technische Assistentin

Tel: +49 731-500 63060
Fax: +49 731-500 63050



Ausgewählte Publikationen / selected publications

  • van Rheenen W, van der Spek RAA, Bakker MK, van Vugt JJFA, Hop PJ, Zwamborn RAJ, de Klein N, Westra HJ, Bakker OB, Deelen P, Shireby G, Hannon E, Moisse M, Baird D, Restuadi R, Dolzhenko E, Dekker AM, Gawor K, Westeneng HJ, Tazelaar GHP, van Eijk KR, Kooyman M, Byrne RP, Doherty M, Heverin M, Al Khleifat A, Iacoangeli A, Shatunov A, Ticozzi N, Cooper-Knock J, Smith BN, Gromicho M, Chandran S, Pal S, Morrison KE, Shaw PJ, Hardy J, Orrell RW, Sendtner M, Meyer T, Başak N, van der Kooi AJ, Ratti A, Fogh I, Gellera C, Lauria G, Corti S, Cereda C, Sproviero D, D'Alfonso S, Sorarù G, Siciliano G, Filosto M, Padovani A, Chiò A, Calvo A, Moglia C, Brunetti M, Canosa A, Grassano M, Beghi E, Pupillo E, Logroscino G, Nefussy B, Osmanovic A, Nordin A, Lerner Y, Zabari M, Gotkine M, Baloh RH, Bell S, Vourc'h P, Corcia P, Couratier P, Millecamps S, Meininger V, Salachas F, Mora Pardina JS, Assialioui A, Rojas-García R, Dion PA, Ross JP, Ludolph AC, Weishaupt JH, Brenner D, Freischmidt A, Bensimon G, Brice A, Durr A, Payan CAM, Saker-Delye S, Wood NW, Topp S, Rademakers R, Tittmann L, Lieb W, Franke A, Ripke S, Braun A, Kraft J, Whiteman DC, Olsen CM, Uitterlinden AG, Hofman A, Rietschel M, Cichon S, Nöthen MM, Amouyel P; SLALOM Consortium; PARALS Consortium; SLAGEN Consortium; SLAP Consortium, Traynor BJ, Singleton AB, Mitne Neto M, Cauchi RJ, Ophoff RA, Wiedau-Pazos M, Lomen-Hoerth C, van Deerlin VM, Grosskreutz J, Roediger A, Gaur N, Jörk A, Barthel T, Theele E, Ilse B, Stubendorff B, Witte OW, Steinbach R, Hübner CA, Graff C, Brylev L, Fominykh V, Demeshonok V, Ataulina A, Rogelj B, Koritnik B, Zidar J, Ravnik-Glavač M, Glavač D, Stević Z, Drory V, Povedano M, Blair IP, Kiernan MC, Benyamin B, Henderson RD, Furlong S, Mathers S, McCombe PA, Needham M, Ngo ST, Nicholson GA, Pamphlett R, Rowe DB, Steyn FJ, Williams KL, Mather KA, Sachdev PS, Henders AK, Wallace L, de Carvalho M, Pinto S, Petri S, Weber M, Rouleau GA, Silani V, Curtis CJ, Breen G, Glass JD, Brown RH Jr, Landers JE, Shaw CE, Andersen PM, Groen EJN, van Es MA, Pasterkamp RJ, Fan D, Garton FC, McRae AF, Davey Smith G, Gaunt TR, Eberle MA, Mill J, McLaughlin RL, Hardiman O, Kenna KP, Wray NR, Tsai E, Runz H, Franke L, Al-Chalabi A, Van Damme P, van den Berg LH, Veldink JH. Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology. Nat Genet. 2021 Dec;53(12):1636-1648.
  • Tang L, Dorst J, Chen L, Liu X, Ma Y, Günther K, Michels S, Müller K, Freischmidt A, Weishaupt JH, Fan D, Ludolph AC. A natural history comparison of SOD1-mutant patients with amyotrophic lateral sclerosis between Chinese and German populations. Transl Neurodegener. 2021 Oct 28;10(1):42.
  • Brenner D, Müller K, Lattante S, Yilmaz R, Knehr A, Freischmidt A, Ludolph AC, Andersen PM, Weishaupt JH. FUS mutations dominate TBK1 mutations in FUS/TBK1 double-mutant ALS/FTD pedigrees. Neurogenetics. 2021 Sep 13. Epub ahead of print.
  • Müller K, Oh KW, Nordin A, Panthi S, Kim SH, Nordin F, Freischmidt A, Ludolph AC, Ki CS, Forsberg K, Weishaupt J, Kim YE, Andersen PM. De novo mutations in SOD1 are a cause of ALS. J Neurol Neurosurg Psychiatry. 2021 Sep 13:jnnp-2021-327520. Epub ahead of print.
  • Ruf WP, Freischmidt A, Grozdanov V, Roth V, Brockmann SJ, Mollenhauer B, Martin D, Haslinger B, Fundel-Clemens K, Otto M, Arnim CV, Holzmann K, Ludolph AC, Weishaupt JH, Danzer KM. Protein Binding Partners of Dysregulated miRNAs in Parkinson's Disease Serum. Cells. 2021 Apr 2;10(4):791.
  • Freischmidt A, Goswami A, Limm K, Zimyanin VL, Demestre M, Glaß H, Holzmann K, Helferich AM, Brockmann SJ, Tripathi P, Yamoah A, Poser I, Oefner PJ, Böckers TM, Aronica E, Ludolph AC, Andersen PM, Hermann A, Weis J, Reinders J, Danzer KM, Weishaupt JH. A serum microRNA sequence reveals fragile X protein pathology in amyotrophic lateral sclerosis. Brain. 2021 May 7;144(4):1214-1229.
  • Sieverding K, Ulmer J, Bruno C, Satoh T, Tsao W, Freischmidt A, Akira S, Wong PC, Ludolph AC, Danzer KM, Lobsiger CS, Brenner D, Weishaupt JH. Hemizygous deletion of Tbk1 worsens neuromuscular junction pathology in TDP-43G298S transgenic mice. Exp Neurol. 2021 Jan;335:113496.
  • Freischmidt A, Brenner D, Ludolph AC, Andersen PM, Weishaupt JH. Commentary: Effects of ALS-associated TANK binding kinase 1 mutations on protein-protein interactions and kinase activity. Front Neurosci. 2020 Sep 11;14:551006.
  • Bruno C, Sieverding K, Freischmidt A, Satoh T, Walther P, Mayer B, Ludolph AC, Akira S, Yilmazer-Hanke D, Danzer KM, Lobsiger CS, Brenner D, Weishaupt JH. Haploinsufficiency of TANK-binding kinase 1 prepones age-associated neuroinflammatory changes without causing motor neuron degeneration in aged mice. Brain Commun. 2020 Aug 21;2(2):fcaa133.
  • Michel D, Danzer KM, Groß R, Conzelmann C, Müller JA, Freischmidt A, Weishaupt JH, Heller S, Münch J, Michel M, Stamminger T, Kleger A, Otto M. Rapid, convenient and efficient kit-independent detection of SARS-CoV-2 RNA. J Virol Methods. 2020 Dec;286:113965.
  • Brenner D, Rosenbohm A, Yilmaz R, Müller K, Grehl T, Petri S, Meyer T, Grosskreutz J, Weydt P, Ruf W, Neuwirth C, Weber M, Pinto S, Claeys KG, Schrank B, Jordan B, Knehr A, Günther K, Hübers A, Zeller D, Kubisch C, Jablonka S, Sendtner M, Klopstock T, de Carvalho M, Sperfeld A, Borck G, Volk AE, Dorst J, Weis J, Otto M, Schuster J, Del Tredici K, Braak H, Danzer KM, Freischmidt A, Meitinger T, Ludolph AC, Andersen PM, Weishaupt JH; German ALS network MND-NET. Reply: Adult-onset distal spinal muscular atrophy: a new phenotype associated with KIF5A mutations. Brain. 2019 Dec 1;142(12):e67.
  • Catanese A, Olde Heuvel F, Mulaw M, Demestre M, Higelin J, Barbi G, Freischmidt A, Weishaupt JH, Ludolph AC, Roselli F, Boeckers TM. Retinoic acid worsens ATG10-dependent autophagy impairment in TBK1-mutant hiPSC-derived motoneurons through SQSTM1/p62 accumulation. Autophagy. 2019 Oct;15(10):1719-1737.
  • Brenner D, Sieverding K, Bruno C, Lüningschrör P, Buck E, Mungwa S, Fischer L, Brockmann SJ, Ulmer J, Bliederhäuser C, Philibert CE, Satoh T, Akira S, Boillée S, Mayer B, Sendtner M, Ludolph AC, Danzer KM, Lobsiger CS, Freischmidt A, Weishaupt JH. Heterozygous Tbk1 loss has opposing effects in early and late stages of ALS in mice. J Exp Med. 2019 Feb 4;216(2):267-278.
  • Helferich AM, Brockmann SJ, Reinders J, Deshpande D, Holzmann K, Brenner D, Andersen PM, Petri S, Thal DR, Michaelis J, Otto M, Just S, Ludolph AC, Danzer KM, Freischmidt A, Weishaupt JH. Dysregulation of a novel miR-1825/TBCB/TUBA4A pathway in sporadic and familial ALS. Cell Mol Life Sci. 2018 Dec;75(23):4301-4319.
  • Naumann M, Pal A, Goswami A, Lojewski X, Japtok J, Vehlow A, Naujock M, Günther R, Jin M, Stanslowsky N, Reinhardt P, Sterneckert J, Frickenhaus M, Pan-Montojo F, Storkebaum E, Poser I, Freischmidt A, Weishaupt JH, Holzmann K, Troost D, Ludolph AC, Boeckers TM, Liebau S, Petri S, Cordes N, Hyman AA, Wegner F, Grill SW, Weis J, Storch A, Hermann A. Impaired DNA damage response signaling by FUS-NLS mutations leads to neurodegeneration and FUS aggregate formation. Nat Commun. 2018 Jan 23;9(1):335.
  • Brenner D, Yilmaz R, Müller K, Grehl T, Petri S, Meyer T, Grosskreutz J, Weydt P, Ruf W, Neuwirth C, Weber M, Pinto S, Claeys KG, Schrank B, Jordan B, Knehr A, Günther K, Hübers A, Zeller D, Kubisch C, Jablonka S, Sendtner M, Klopstock T, de Carvalho M, Sperfeld A, Borck G, Volk AE, Dorst J, Weis J, Otto M, Schuster J, Del Tredici K, Braak H, Danzer KM, Freischmidt A, Meitinger T, Strom TM, Ludolph AC, Andersen PM, Weishaupt JH; German ALS network MND-NET. Hot-spot KIF5A mutations cause familial ALS. Brain. 2018 Mar 1;141(3):688-697.
  • Brockmann SJ, Freischmidt A, Oeckl P, Müller K, Ponna SK, Helferich AM, Paone C, Reinders J, Kojer K, Orth M, Jokela M, Auranen M, Udd B, Hermann A, Danzer KM, Lichtner P, Walther P, Ludolph AC, Andersen PM, Otto M, Kursula P, Just S, Weishaupt JH. CHCHD10 mutations p.R15L and p.G66V cause motoneuron disease by haploinsufficiency. Hum Mol Genet. 2018 Feb 15;27(4):706-715.
  • Freischmidt A, Müller K, Ludolph AC, Weishaupt JH, Andersen PM. Association of Mutations in TBK1 With Sporadic and Familial Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. JAMA Neurol. 2017 Jan 1;74(1):110-113.
  • Zondler L, Feiler MS, Freischmidt A, Ruf WP, Ludolph AC, Danzer KM, Weishaupt JH. Impaired activation of ALS monocytes by exosomes. Immunol Cell Biol. 2017 Feb;95(2):207-214.
  • Zondler L, Müller K, Khalaji S, Bliederhäuser C, Ruf WP, Grozdanov V, Thiemann M, Fundel-Clemes K, Freischmidt A, Holzmann K, Strobel B, Weydt P, Witting A, Thal DR, Helferich AM, Hengerer B, Gottschalk KE, Hill O, Kluge M, Ludolph AC, Danzer KM, Weishaupt JH. Peripheral monocytes are functionally altered and invade the CNS in ALS patients. Acta Neuropathol. 2016 Sep;132(3):391-411.
  • Bliederhaeuser C, Grozdanov V, Speidel A, Zondler L, Ruf WP, Bayer H, Kiechle M, Feiler MS, Freischmidt A, Brenner D, Witting A, Hengerer B, Fändrich M, Ludolph AC, Weishaupt JH, Gillardon F, Danzer KM. Age-dependent defects of alpha-synuclein oligomer uptake in microglia and monocytes. Acta Neuropathol. 2016 Mar;131(3):379-91.
  • Helferich AM, Ruf WP, Grozdanov V, Freischmidt A, Feiler MS, Zondler L, Ludolph AC, McLean PJ, Weishaupt JH, Danzer KM. α-synuclein interacts with SOD1 and promotes its oligomerization. Mol Neurodegener. 2015 Dec 8;10:66.
  • Feiler MS, Strobel B, Freischmidt A, Helferich AM, Kappel J, Brewer BM, Li D, Thal DR, Walther P, Ludolph AC, Danzer KM, Weishaupt JH. TDP-43 is intercellularly transmitted across axon terminals. J Cell Biol. 2015 Nov 23;211(4):897-911.
  • Freischmidt A, Schöpflin M, Feiler MS, Fleck AK, Ludolph AC, Weishaupt JH. Profilin 1 with the amyotrophic lateral sclerosis associated mutation T109M displays unaltered actin binding and does not affect the actin cytoskeleton. BMC Neurosci. 2015 Nov 16;16:77.
  • Freischmidt A, Müller K, Zondler L, Weydt P, Mayer B, von Arnim CA, Hübers A, Dorst J, Otto M, Holzmann K, Ludolph AC, Danzer KM, Weishaupt JH. Serum microRNAs in sporadic amyotrophic lateral sclerosis. Neurobiol Aging. 2015 Sep;36(9):2660.e15-20.
  • Freischmidt A, Wieland T, Richter B, Ruf W, Schaeffer V, Müller K, Marroquin N, Nordin F, Hübers A, Weydt P, Pinto S, Press R, Millecamps S, Molko N, Bernard E, Desnuelle C, Soriani MH, Dorst J, Graf E, Nordström U, Feiler MS, Putz S, Boeckers TM, Meyer T, Winkler AS, Winkelman J, de Carvalho M, Thal DR, Otto M, Brännström T, Volk AE, Kursula P, Danzer KM, Lichtner P, Dikic I, Meitinger T, Ludolph AC, Strom TM, Andersen PM, Weishaupt JH. Haploinsufficiency of TBK1 causes familial ALS and fronto-temporal dementia. Nat Neurosci. 2015 May;18(5):631-6.
  • Kunadt M, Eckermann K, Stuendl A, Gong J, Russo B, Strauss K, Rai S, Kügler S, Falomir Lockhart L, Schwalbe M, Krumova P, Oliveira LM, Bähr M, Möbius W, Levin J, Giese A, Kruse N, Mollenhauer B, Geiss-Friedlander R, Ludolph AC, Freischmidt A, Feiler MS, Danzer KM, Zweckstetter M, Jovin TM, Simons M, Weishaupt JH, Schneider A. Extracellular vesicle sorting of α-Synuclein is regulated by sumoylation. Acta Neuropathol. 2015 May;129(5):695-713.
  • Freischmidt A, Müller K, Zondler L, Weydt P, Volk AE, Božič AL, Walter M, Bonin M, Mayer B, von Arnim CA, Otto M, Dieterich C, Holzmann K, Andersen PM, Ludolph AC, Danzer KM, Weishaupt JH. Serum microRNAs in patients with genetic amyotrophic lateral sclerosis and pre-manifest mutation carriers. Brain. 2014 Nov;137(Pt 11):2938-50.
  • Rizik N, Freischmidt A, Ludolph AC, Weishaupt JH. FXN GAA repeat expansions in amyotrophic lateral sclerosis. J Clin Neurosci. 2014 Aug;21(8):1319-22.
  • Freischmidt A, Müller K, Ludolph AC, Weishaupt JH. Systemic dysregulation of TDP-43 binding microRNAs in amyotrophic lateral sclerosis. Acta Neuropathol Commun. 2013 Jul 30;1:42.
  • Freischmidt A, Hiltl J, Kalbitzer HR, Horn-Katting G. Enhanced in vitro translation at reduced temperatures using a cold-shock RNA motif. Biotechnol Lett. 2013 Mar;35(3):389-95.


  • Freischmidt A, Liss M, Wagner R, Kalbitzer HR, Horn G. RNA secondary structure and in vitro translation efficiency. Protein Expr Purif. 2012 Mar;82(1):26-31.


  • Freischmidt A, Meysing M, Liss M, Wagner R, Kalbitzer HR, Horn G. Limiting factors of the translation machinery. J Biotechnol. 2010 Oct 1;150(1):44-50.



Telefon 0731 500 63073

Telefax 0731 500 63050

Dr. rer. nat. Axel Freischmidt
Neurology Department
Ulm University
Albert-Einstein-Allee 11
89081 Ulm