Anna-Lena StrömDocent

Molecular mechanisms behind neurodegeneration

Neurodegenerative diseases like Amyotrophic lateral sclerosis (ALS), Alzheimer’s and polyglutamine diseases are characterized by the gradual loss of neurons in the central nervous system (CNS). While these disorders are distinct in their clinical manifestations, they share common pathological hallmarks like protein misfolding and aggregation, as well as oxidative stress. Using various models, in combination with molecular biology, biochemical and immunological techniques, our overall aim is to identify and characterize factors/mechanisms which contribute to protein aggregation and neurotoxicity in neurodegenerative diseases, as well as to explore molecular strategies by which these factors/mechanisms can be counteracted. We are currently working on two main research topics:

 

1. Disruption of RNA-binding proteins in SCA7 polyglutamine disease

Polyglutamine (polyQ) diseases are inherited disorders caused by expansion of trinucleotide (CAG) repeats, which are translated to abnormally elongated glutamine (Q) tracts in the respective mutant proteins. To date nine polyQ diseases, including Huntington’s disease (HD) and six spinocerebellar ataxias (SCA 1, 2, 3, 6, 7, and 17) have been identified. In SCA7 the polyQ domain is located in the ATXN7 protein and due to a founder effect this disease occurs with an unusual high prevalence in Sweden. Common disease mechanism(s), where the expanded glutamine domain confers toxic gain-of-function to the respective disease proteins, has been suggested for polyQ diseases. These mechanisms include sequestration and disruption of other essential proteins, like p53, into polyQ protein aggregates. Currently we are studying how polyQ expanded ATXN7 affects the localization and function of different RNA-binding proteins (RBPs). RBPs regulate a number of essential cellular functions including transcription, mRNA splicing and stability, as well as the cellular stress response.  

 

2. Regulation of Amyloid precursor protein (APP) processing

Abnormal accumulation of the amyloid-β (Aβ) peptide is a hallmark in Alzheimer’s disease and thought to play a key role in disease pathology. Aβ is produced by regulated intramembrane-proteolysis (RIP) of the amyloid precursor protein (APP). APP processing can occur through two pathways; the non-amyloidogenic (α-secretase) and the Aβ producing amylodiogenic (β-secretase) pathway. We are studying mechanisms/factors that regulate APP processing and are especially interested in promoting the a-secretase pathway, which will consequently decrease the Aβ production. One factor that we study is the brain enriched adaptor protein Fe65, which can directly bind to APP.

 

Group members

Frida Niss, PhD student

Rebecca Revol, PhD student

 

PhD Dissertations from the group

Abiodun Ajayi: "Molecular mechanism(s) underlying neurodegeneration in SCA7 disease: Role of NOX enzymes and oxidative stress" (2015)

Xin Yu: "Studies of polyglutamine expanded Ataxin-7 toxicity" (2015)

Fredrik Jeppsson: "Characterization of Diagnostic Tools and Potential Treatments for Alzheimer's Disease - PET ligands and BACE1 inhibitors" (2016)

Niina Koistinen: "The amyloid-Beta precursor protein (APP)-binding protein Fe65 and APP processing" (2018)

Preeti Menon: "The amyloid-Beta precursor protein (APP) and its adaptor protein Fe65" (2020)

 

Selected publications:

• Menon P, Koistinen N,  Iverfeldt K and Ström AL. (2019). Phosphorylation of the Amyloid Precursor Protein (APP) at Ser-675 Promotes APP Processing Involving Meprin β. JBC 294 (47), 17768-17776

• Bergqvist C, Figueroa RA, Niss F, Beckman M, Maksel D, Jafferali MH, Kulyte A, Ström AL, and Hallberg, E. (2019). Monitoring of chromatin organization in live cells by FRIC. Nucleic acid research May 21;47(9).

• Klionsky DJ, Abdelmohsen K, Abe A, Abedin MJ, Abeliovich H,……………Ström AL, et al#.. (2016). Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy. Jan 2;12(1):1-222. # This article has many more authors which have not been listed

• Ajayi A., Yu, X., Wahlo-Svedin C., Tsirigotaki G., Karlström V., and Ström AL.(2015). Altered p53 and NOX1 activity cause bioenergetic defects in a SCA7 polyglutamine disease model. BBA Bioenergetics, 1847(4-5); 418–428

• Yu X., Muñoz-Alarcón A., Ajayi A., Webling K., Steinhof, A., Langel Ü. and Ström AL. (2013). Inhibition of autophagy via p53-mediated disruption of ULK1 in a SCA7 polyglutamine disease model. Journal of Molecular Neuroscience, in press. DOI: 10.1007/s12031-013-0012-x

• Ajayi A., Yu X. and Ström AL. (2013). The role of NADPH oxidase (NOX) enzymes in neurodegenerative disease. Review article in Frontiers in Biology, 8(2): 175–188

• Ajayi A., Yu X., Lindberg S., Langel Ü. and Ström AL. (2012). Expanded ataxin-7 cause toxicity by inducing ROS production from NADPH oxidase complexes in a stable inducible Spinocerebellar ataxia type 7 (SCA7) model. BMC Neuroscience 2012, 13:86.

• Yu X., Ajayi A., Boga NR. and Ström AL. (2012). Differential Degradation of Full-length and Cleaved Ataxin-7 Fragments in a Novel Stable Inducible SCA7 Model. Journal of Molecular Neuroscience, Jun;47(2):219-33.

• Shi P., Ström AL., Gal J. and Zhu H.. (2010). Effects of ALS-related SOD1 mutants on dynein- and KIF5-mediated retrograde and anterograde axonal transport. Biochem Biophys Acta, 2010, Sep;1802(9):707-716

• Ström A-L.,  Shi P., Zhang F., Gal J., KiltyR., HaywardL. and Zhu H.. Interaction with dynein-mediated retrograde transport system facilitates formation of large aggregates / inclusions of familial ALS SOD1 mutants. JBC, 2008, Aug 15;283(33):22795-805.

• Gal J., Ström A-L., Kilty R., Zhang F. and Zhu H.. p62/Sequestosome 1 is upregulated and enhances aggregate formation in model systems of familiar amyotrophic lateral sclerosis. JBC, 2007, Apr 13;282(15):11068-77.

• Zhang F., Ström A-L., Fukada K., Lee S., Hayward L. and Zhu H.. Interactions between familial ALS-linked SOD1 mutants and the dynein complex: Implications of retrograde axonal transport in ALS. JBC, 2007, Jun 1;282(22):16691-9.

• Ström A-L., Forsgren, L. and Holmberg, M.. A role for both expanded and wild type ataxin-7 in transcriptional regulation. Neurobiology of Disease, 2005, 20(3):646-55.
• Jonasson J, Ström A-L., Hart P., Brännström T., Forsgren L. and Holmberg M.. Expression of ataxin-7 in CNS and non-CNS tissue of normal and SCA7 individuals. Acta Neuropathologica, 2002, 104(1): 29-37.