The nuclear envelope proteins Kugelkern and Narf and their putative role in aging

by Maria Kriebel
Doctoral thesis
Date of Examination:2018-03-13
Date of issue:2018-10-26
Advisor:Prof. Dr. Jörg Großhans
Referee:Prof. Dr. Reinhard Schuh
Referee:Prof. Dr. Harald Hermann-Lerdon
Referee:Prof. Dr. Gregor Bucher
Referee:Prof. Dr. Bernd Wollnik
Referee:PD Dr. Halyna Shcherbata
Persistent Address: http://dx.doi.org/10.53846/goediss-7115

 

 

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Abstract

English

Lamins are type V intermediate filaments and represent the major constituent of the nuclear lamina. Mutations in the laminA/C gene as well as in other nuclear envelope associated proteins lead to a series of human genetic disorders, so-called laminopathies. The most prominent laminopathy is the Hutchinson-Gilford progeria syndrome (HGPS). HGPS patients appear prematurely aged developing aging-related conditions such as osteoporosis, loss of subcutaneous fat and cardiovaskular disease already during childhood. Many of the HGPS patients contain a single point mutation in the lamin A/C gene which affects the maturation process and leads to the expression of a permanently farnesylated Prelamin A, called Progerin. Progerin accumulates at the nuclear periphery and leads to a variety of cellular and nuclear defects like a disorganization of heterochromatin structure, an increase in DNA damage and defects in nuclear morphology. Despite the insights in the clinical symptoms and the genetic basis of HGPS and other laminopathies, the molecular and cellular mechanism that leads to accelerated aging is unknown and remains a topic of ongoing research. The Großhans lab has developed a HGPS model in Drosophila, using lamin Dm0 and Kuk, a nuclear protein which shares structural and functional features to lamins. As farnesylation plays a major role in the disease mechanism, I screened for genetic and biochemical interaction partners of Kuk. I focused on Narf, which has previously been identified as a Lamin binding partner that depends on farnesylation. Furthermore a dominant de novo mutation was recently identified within the human Narf protein causing HGPS related symptoms (Prof. Wollnik, personal communication). Narf is an evolutionary conserved protein with a homologue in Drosophila. As Narf is thought to interact specifically with the farnesylated Prelamin A in humans, I hypothesized that Narf interacts with Lamin Dm0 or Kugelkern in Drosophila. Beside mapping and complementation analysis, nothing was known about the function of Narf in Drosophila. In order to study the cell biological and developmental functions of Narf, I established Drosophila as a model system. I characterized point mutations and generated several tools like an antibody as well as genomic and inducible transgenes. Narf localizes to the nuclear envelope and is essential for development as well as during adulthood. Narf function may rely to its role in Fe-S protein maturation. I demonstrated that Narf is involved in aging-related processes as loss-of function experiments decreased Drosophila`s lifespan whereas constitutively higher expression by multiple genomic copies or UAS overexpression led to a prolongation in lifespan. How Narf might contribute to these processes is not clear yet. RNA sequencing analyses points to a role in oxidative stress response. My data suggest a role of Narf in the regulation of stress defense mechanisms which are required for the maintenance of a cellular redox homeostasis needed for aging.
Keywords: Drosophila; Aging; Narf; Kugelkern
 
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